Therapeutic Properties and Biological Benefits of Marine-Derived Anticancer Peptides

Various organisms exist in the oceanic environment. These marine organisms provide an abundant source of potential medicines. Many marine peptides possess anticancer properties, some of which have been evaluated for treatment of human cancer in clinical trials. Marine anticancer peptides kill cancer cells through different mechanisms, such as apoptosis, disruption of the tubulin-microtubule balance, and inhibition of angiogenesis. Traditional chemotherapeutic agents have side effects and depress immune responses. Thus, the research and development of novel anticancer peptides with low toxicity to normal human cells and mechanisms of action capable of avoiding multi-drug resistance may provide a new method for anticancer treatment. This review provides useful information on the potential of marine anticancer peptides for human therapy.


Introduction
The oceans are a diverse environment comprising about 75% of living organisms [1]. The oceanic environment is an abundant source of nutraceuticals and potential candidates with therapeutic functions [2].
Cancer is among the major causes of death with high morbidity and mortality [3]. Cell division that occurs within the cell tissue is a normal process. Under normal conditions, apoptosis constantly maintains the equilibrium between proliferating cells and programmed cell death. Additionally, DNA mutations cause cancer by interruption of the regulating programs. In carcinogenesis, normal cells are transformed into cancer cells [4,5]. In recent decades, marine compounds were studied for the treatment of cancer. Various types of marine products, such as alkaloids, polyketides, terpenes, peptides, and carbohydrates, have the potential to prevent and cure cancer [6]. Therefore, these products may be important in the development of anticancer drugs [7].
In recent years, novel peptides with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis, and antiviral activities have been found in marine organisms and studied [2]. Many marine peptides also possess anticancer activity. Some of these peptides have been studied as cancer treatment in human clinical trials [8][9][10]. Marine anticancer peptides can kill cancer cells through different mechanisms, such as apoptosis, affecting the tubulin-microtubule imbalance, and inhibition of angiogenesis [11]. Understanding the structure and function of pharmacologically active marine-derived anticancer peptides will enhance the development of lead drug candidates.
This review focuses on the function and structure of pharmacologically active marine peptides with anticancer activity. Research on peptides derived from marine sources is underway to develop new potential cancer treatments.  10-50 nM (neuro-2a), GI 50 < 10 nM (NCI 60 cell line panel) [36,37] Bisebromoamide (8) Cyanobacteria:

Diplosoma virens
Linear tripeptides Apoptosis /in vitro only IC 50 : 5-10 µg/mL (P388, A549, HT29, CV1) [133] Vitilevuamide (98) Ascidia: Didemnum cuculiferum, Polysyncranton lithostrotum Ziconotide (104) Mollusk: Conus magus Linear peptide Selective N-type calcium channel blocker/FDA approved IC 50 : 100 nM (HEK), 10 nM (IMR32) [158][159][160][161] Pardaxin (105) Fish: Pardachirus marmoratus Linear peptide Caspase-dependent and ROS-mediated Apoptosis /active in animal IC 90 : 13 µg/mL (NH-11) [162,163] YALRAH (106) Fish: Setipinna taty Linear peptide Antiproliferative activity/in vitro only IC 50 : 11.1 µM (PC3) [164] Dose-dependent DNA content analysis and gene expression profiling of apratoxin A revealed critical inhibition of cell division, delay in the G1 stage cell cycle arrest, and apoptosis-induced cell death. Apratoxin A was found to inhibit fibroblast growth factor receptor (FGFR) signaling pathway, which is generally associated with cancer [35]. Also, it prevented phosphorylation or activation of signal transducer and activator of transcription 3 (STAT3), a downstream transcriptional effector of FGFR signaling, in the functional genome approach [35]. STAT3 is expressed and activated in a broad range of cancers, which makes it an important anticancer drug target [35]. Because FGF is important for cell proliferation and angiogenesis, the inactivation of STAT3 occurs through angiogenesis mediated by the FGF signaling pathway and initiates the apoptotic cascade [35]. On the basis of proteomic studies, apratoxin A inhibits the N-glycosylation of endoplasmic reticulum receptors, thereby depleting cancer-associated receptor tyrosine kinases only in cancer cells [29]. Dose-dependent DNA content analysis and gene expression profiling of apratoxin A revealed critical inhibition of cell division, delay in the G1 stage cell cycle arrest, and apoptosis-induced cell death. Apratoxin A was found to inhibit fibroblast growth factor receptor (FGFR) signaling pathway, which is generally associated with cancer [35]. Also, it prevented phosphorylation or activation of signal transducer and activator of transcription 3 (STAT3), a downstream transcriptional effector of FGFR signaling, in the functional genome approach [35]. STAT3 is expressed and activated in a broad range of cancers, which makes it an important anticancer drug target [35]. Because FGF is important for cell proliferation and angiogenesis, the inactivation of STAT3 occurs through angiogenesis mediated by the FGF signaling pathway and initiates the apoptotic cascade [35]. On the basis of proteomic studies, apratoxin A inhibits the N-glycosylation of endoplasmic reticulum receptors, thereby depleting cancer-associated receptor tyrosine kinases only in cancer cells [29].

Aurilides
The aurilides (5)(6)(7) are cyclic depsipeptides containing a polyketoide that is part of a macrocyclic carbon skeleton and six amino acid-derived moieties ( Figure 2) [36,37]. Aurilide (5) was isolated from the Dolabella auricularia in Japanese sea hare, whereas aurilide B (6) and C (7) were isolated from the oceanic cyanobacterium Lyngbya majuscula in the Papua New Guinea collection [36,37]. Aurilide B and C exhibited in vitro cytotoxicity against NCI-H460 (LC50 of 40 and 130 nM, respectively) and the neuro-2a mouse neuroblastoma cell line (LC50 of 10 and 50 nM, respectively) [37]. The effect of aurilide B on the NCI 60 cell line panel was also analyzed and it was found to exhibit high cytotoxicity with a 50% growth inhibition (GI50) value of less than 10 nM in the leukemia cell line and renal and prostate cancer cell lines [37]. The net tumor cell killing activity of aurilide B was confirmed by the National Cancer Institute (NCI)'s hollow fiber assay for preliminary in vivo screening of novel anticancer drugs.  (5), aurilide B (6), and aurilide C (7) [36,37].

Aurilides
The aurilides (5)(6)(7) are cyclic depsipeptides containing a polyketoide that is part of a macrocyclic carbon skeleton and six amino acid-derived moieties ( Figure 2) [36,37]. Aurilide (5) was isolated from the Dolabella auricularia in Japanese sea hare, whereas aurilide B (6) and C (7) were isolated from the oceanic cyanobacterium Lyngbya majuscula in the Papua New Guinea collection [36,37]. Aurilide B and C exhibited in vitro cytotoxicity against NCI-H460 (LC 50 of 40 and 130 nM, respectively) and the neuro-2a mouse neuroblastoma cell line (LC 50 of 10 and 50 nM, respectively) [37]. The effect of aurilide B on the NCI 60 cell line panel was also analyzed and it was found to exhibit high cytotoxicity with a 50% growth inhibition (GI 50 ) value of less than 10 nM in the leukemia cell line and renal and prostate cancer cell lines [37]. The net tumor cell killing activity of aurilide B was confirmed by the National Cancer Institute (NCI)'s hollow fiber assay for preliminary in vivo screening of novel anticancer drugs. Dose-dependent DNA content analysis and gene expression profiling of apratoxin A revealed critical inhibition of cell division, delay in the G1 stage cell cycle arrest, and apoptosis-induced cell death. Apratoxin A was found to inhibit fibroblast growth factor receptor (FGFR) signaling pathway, which is generally associated with cancer [35]. Also, it prevented phosphorylation or activation of signal transducer and activator of transcription 3 (STAT3), a downstream transcriptional effector of FGFR signaling, in the functional genome approach [35]. STAT3 is expressed and activated in a broad range of cancers, which makes it an important anticancer drug target [35]. Because FGF is important for cell proliferation and angiogenesis, the inactivation of STAT3 occurs through angiogenesis mediated by the FGF signaling pathway and initiates the apoptotic cascade [35]. On the basis of proteomic studies, apratoxin A inhibits the N-glycosylation of endoplasmic reticulum receptors, thereby depleting cancer-associated receptor tyrosine kinases only in cancer cells [29].

Aurilides
The aurilides (5-7) are cyclic depsipeptides containing a polyketoide that is part of a macrocyclic carbon skeleton and six amino acid-derived moieties ( Figure 2) [36,37]. Aurilide (5) was isolated from the Dolabella auricularia in Japanese sea hare, whereas aurilide B (6) and C (7) were isolated from the oceanic cyanobacterium Lyngbya majuscula in the Papua New Guinea collection [36,37]. Aurilide B and C exhibited in vitro cytotoxicity against NCI-H460 (LC50 of 40 and 130 nM, respectively) and the neuro-2a mouse neuroblastoma cell line (LC50 of 10 and 50 nM, respectively) [37]. The effect of aurilide B on the NCI 60 cell line panel was also analyzed and it was found to exhibit high cytotoxicity with a 50% growth inhibition (GI50) value of less than 10 nM in the leukemia cell line and renal and prostate cancer cell lines [37]. The net tumor cell killing activity of aurilide B was confirmed by the National Cancer Institute (NCI)'s hollow fiber assay for preliminary in vivo screening of novel anticancer drugs.
Bisebromoamide is a strong cytotoxin with an IC50 value of 40 ng/mL in HeLa S3 cells. Also, for a panel of 39 human cancer cell lines (JFCR39), it showed an average GI50 value of 40 nM. Moreover, a wealth of experimental data demonstrated that the extracellular signal-regulated protein kinase (ERK) signaling cascade recognized its targets through interaction with bisebromoamide [38].

Coibamide A
Coibamide A (9) was isolated from Leptolyngbya sp., a Panamanian marine cyanobacterium, which is a cyclic depsipeptide ( Figure 4) [39]. Testing of coibamide A in the NCI-H460 lung cancer cells and mouse neuro-2a cells showed strong cytotoxicity with LC50 values of less than 23 nM. Furthermore, coibamide A, a powerful cancer cell toxin with an unique selectivity for the NCI 60 cancer cell line panel, showed significant cytotoxicity against HL-60 human myeloid cells, LOX IMVI human melanoma cell, MDA-MB-231 breast cancer cells and SNB-75 cells with low nM potency. In addition, powerful anti-proliferative activity of the cancer cell was found via a novel target or mechanism of action using COMPARE assays [39].

Cryptophycin
Cryptophycin (10) was isolated from the marine cyanobacteria Nostoc sp. ATCC 53789 and GSV 224 and is a depsipeptide with potent antifungal activity ( Figure 5) [40]. Cryptophycin bound strongly to the microtubule ends at the vinca-binding site and inhibited the microtubule polymerization. It showed marked cytotoxicity with an IC50 value of less than 50 pM for multidrug-resistant (MDR) tumor cell lines [41].
The synthetic derivative of cryptophycin, cryptophycin-52 (LY355703), is produced by total synthesis. Cryptophycin-52 induced apoptosis, which is confirmed through the hyperphosphorylation of Bcl-2, cell cycle arrest, and growth inhibition in preclinical trials for the in vitro human non-small cell lung carcinoma (NSCLC) cell line [42]. A clinical phase II study of cryptophycin-52 revealed the

Coibamide A
Coibamide A (9) was isolated from Leptolyngbya sp., a Panamanian marine cyanobacterium, which is a cyclic depsipeptide ( Figure 4) [39]. Testing of coibamide A in the NCI-H460 lung cancer cells and mouse neuro-2a cells showed strong cytotoxicity with LC 50 values of less than 23 nM. Furthermore, coibamide A, a powerful cancer cell toxin with an unique selectivity for the NCI 60 cancer cell line panel, showed significant cytotoxicity against HL-60 human myeloid cells, LOX IMVI human melanoma cell, MDA-MB-231 breast cancer cells and SNB-75 cells with low nM potency. In addition, powerful anti-proliferative activity of the cancer cell was found via a novel target or mechanism of action using COMPARE assays [39].  (8) is a linear peptide that is a marine toxic substance isolated from Lyngbya sp. in the Okinawan collection ( Figure 3) [38]. Bisebromoamide consists of the N-pivaloyl-alanine, N-methyl-3-bromo-tyrosine, 4-methylproline, 2-(1-oxo-propyl)-pyrrolidine and 2-methylcystine, leucine, N-methylphenyl-alanine.
Bisebromoamide is a strong cytotoxin with an IC50 value of 40 ng/mL in HeLa S3 cells. Also, for a panel of 39 human cancer cell lines (JFCR39), it showed an average GI50 value of 40 nM. Moreover, a wealth of experimental data demonstrated that the extracellular signal-regulated protein kinase (ERK) signaling cascade recognized its targets through interaction with bisebromoamide [38].

Coibamide A
Coibamide A (9) was isolated from Leptolyngbya sp., a Panamanian marine cyanobacterium, which is a cyclic depsipeptide ( Figure 4) [39]. Testing of coibamide A in the NCI-H460 lung cancer cells and mouse neuro-2a cells showed strong cytotoxicity with LC50 values of less than 23 nM. Furthermore, coibamide A, a powerful cancer cell toxin with an unique selectivity for the NCI 60 cancer cell line panel, showed significant cytotoxicity against HL-60 human myeloid cells, LOX IMVI human melanoma cell, MDA-MB-231 breast cancer cells and SNB-75 cells with low nM potency. In addition, powerful anti-proliferative activity of the cancer cell was found via a novel target or mechanism of action using COMPARE assays [39].

Cryptophycin
Cryptophycin (10) was isolated from the marine cyanobacteria Nostoc sp. ATCC 53789 and GSV 224 and is a depsipeptide with potent antifungal activity ( Figure 5) [40]. Cryptophycin bound strongly to the microtubule ends at the vinca-binding site and inhibited the microtubule polymerization. It showed marked cytotoxicity with an IC50 value of less than 50 pM for multidrug-resistant (MDR) tumor cell lines [41].
The synthetic derivative of cryptophycin, cryptophycin-52 (LY355703), is produced by total synthesis. Cryptophycin-52 induced apoptosis, which is confirmed through the hyperphosphorylation of Bcl-2, cell cycle arrest, and growth inhibition in preclinical trials for the in vitro human non-small cell lung carcinoma (NSCLC) cell line [42]. A clinical phase II study of cryptophycin-52 revealed the

Cryptophycin
Cryptophycin (10) was isolated from the marine cyanobacteria Nostoc sp. ATCC 53789 and GSV 224 and is a depsipeptide with potent antifungal activity ( Figure 5) [40]. Cryptophycin bound strongly to the microtubule ends at the vinca-binding site and inhibited the microtubule polymerization. It showed marked cytotoxicity with an IC 50 value of less than 50 pM for multidrug-resistant (MDR) tumor cell lines [41].
The synthetic derivative of cryptophycin, cryptophycin-52 (LY355703), is produced by total synthesis. Cryptophycin-52 induced apoptosis, which is confirmed through the hyperphosphorylation of Bcl-2, cell cycle arrest, and growth inhibition in preclinical trials for the in vitro human non-small cell lung carcinoma (NSCLC) cell line [42]. A clinical phase II study of cryptophycin-52 revealed the antitumor effect in advanced NSCLC and platinum-resistant advanced ovarian cancer in patients [43,44]. antitumor effect in advanced NSCLC and platinum-resistant advanced ovarian cancer in patients [43,44]. 3.1.6. Desmethoxymajusculamide C Desmethoxymajusculamide C (11) is a cyclic depsipeptide produced by the L. majuscula. It has strong and selective antitumor activity when tested against HCT-116 human colon carcinoma cells as demonstrated by an IC50 of 20 nM and the destruction of cell microfibrils networks ( Figure 6) [45]. In the disk diffusion assay, linear desmethoxymajusculamide C maintained powerful actin depolymerization ability as well as solid tumor selectivity [45].
Grassypeptolide D (15) and E (16) exhibit potent cytotoxicity against HeLa (IC50 = 335 and 192 nM, respectively) and mouse neuro-2a blastoma cells (IC50 = 599 and 407 nM, respectively) ( Figure 7) [47].  3.1.6. Desmethoxymajusculamide C Desmethoxymajusculamide C (11) is a cyclic depsipeptide produced by the L. majuscula. It has strong and selective antitumor activity when tested against HCT-116 human colon carcinoma cells as demonstrated by an IC 50 of 20 nM and the destruction of cell microfibrils networks ( Figure 6) [45]. In the disk diffusion assay, linear desmethoxymajusculamide C maintained powerful actin depolymerization ability as well as solid tumor selectivity [45]. antitumor effect in advanced NSCLC and platinum-resistant advanced ovarian cancer in patients [43,44]. In the disk diffusion assay, linear desmethoxymajusculamide C maintained powerful actin depolymerization ability as well as solid tumor selectivity [45].

Grassypeptolides
Grassypeptolides A-C (12-16) are cyclic depsipeptides containing bis-thiazoline and were isolated from Lyngbya confervoides [46]. Grassypeptolides also contains an unusual β-amino acid (2-methyl-3-aminobutyric acid), many D-amino acids, and a number of N-methylated amino acids. When the ethyl substituent of Grassypeptolide A (12) (IC 50 = 1.22 and 1.01 µM against HT29 and HeLa cancer cell lines, respectively) turned to the methyl group in grassypeptolide B (13), the activity decreases to an extent (3-4-fold; IC 50 = 4.97 and 2.93 µM), while the reversal of the Phe unit adjacent to the bis-thiazoline moiety (grassypeptolide C (14)) results in 16-23 fold greater efficacy (IC 50 = 76.7 and 44.6 nM) (Figure 7) [46]. Grassypeptolide A and C induce G1 cell cycle arrest at lower concentrations and induce G2/M cell-cycle arrest at higher concentrations in HeLa cells [46]. antitumor effect in advanced NSCLC and platinum-resistant advanced ovarian cancer in patients [43,44]. 3.1.6. Desmethoxymajusculamide C Desmethoxymajusculamide C (11) is a cyclic depsipeptide produced by the L. majuscula. It has strong and selective antitumor activity when tested against HCT-116 human colon carcinoma cells as demonstrated by an IC50 of 20 nM and the destruction of cell microfibrils networks ( Figure 6) [45]. In the disk diffusion assay, linear desmethoxymajusculamide C maintained powerful actin depolymerization ability as well as solid tumor selectivity [45].
The pharmacological target for hectochlorin has been proposed as actin microfilaments owing to the cumulation of CA46 cells in the G2/M phase. Subsequently, hectochlorin induced actin polymerization with a half-maximal effective concentration (EC50) value of 20 μM in PtK2 cells. Among the NCI 60 cancer cell lines, 23 cancer cell lines such as colon melanoma, ovarian tumor, and renal cells showed strong cytotoxicity. Hectochlorin (18) showed cytotoxic activity with IC50 values of 20 and 300 nM for CA46 human Burkitt lymphoma cell and PtK2 cells, respectively [51]. However, the dose-response curve of hectochlorin was flat, suggesting that hectochlorin is more antiproliferative than cytotoxic [51].
The pharmacological target for hectochlorin has been proposed as actin microfilaments owing to the cumulation of CA46 cells in the G2/M phase. Subsequently, hectochlorin induced actin polymerization with a half-maximal effective concentration (EC 50 ) value of 20 µM in PtK2 cells. Among the NCI 60 cancer cell lines, 23 cancer cell lines such as colon melanoma, ovarian tumor, and renal cells showed strong cytotoxicity. Hectochlorin (18) showed cytotoxic activity with IC 50 values of 20 and 300 nM for CA46 human Burkitt lymphoma cell and PtK2 cells, respectively [51]. However, the dose-response curve of hectochlorin was flat, suggesting that hectochlorin is more antiproliferative than cytotoxic [51].  Figure 8) [48]. Hantupeptin A is a 19-membered cyclic tetrapeptide, which consists of α-amino acids, α-hydroxy acid residue (either phenyl lactic acid, proline, N-methylvaline, valine, or N-methylisoleucine), and an α-methyl-β-hydroxy acid unit with an alkyne at the C-terminal end. The hydroxyl group is attached on the carbon (C-35) of an unusual hydroxy acid, 3-hydroxy-2-methyloctynoic acid [49,50]. Hantupeptin A has shown cytotoxicity with IC50 values of 32 nM and 4.0 μM when tested against MOLT-4 leukemia and MCF-7 breast cancer cells, respectively [49,50].
The pharmacological target for hectochlorin has been proposed as actin microfilaments owing to the cumulation of CA46 cells in the G2/M phase. Subsequently, hectochlorin induced actin polymerization with a half-maximal effective concentration (EC50) value of 20 μM in PtK2 cells. Among the NCI 60 cancer cell lines, 23 cancer cell lines such as colon melanoma, ovarian tumor, and renal cells showed strong cytotoxicity. Hectochlorin (18) showed cytotoxic activity with IC50 values of 20 and 300 nM for CA46 human Burkitt lymphoma cell and PtK2 cells, respectively [51]. However, the dose-response curve of hectochlorin was flat, suggesting that hectochlorin is more antiproliferative than cytotoxic [51].

Lagunamides
The cyclodepsipeptides lagunamide A (22) and B (23) were isolated from the filamentous marine cyanobacterium L. majuscule. These compounds were cytotoxic against P388 murine leukemia cell lines with IC50 values of 6.4-20.5 nM, respectively ( Figure 12) [54]. Furthermore, a biochemical analysis using HCT8 and MCF7 cancer cells indicated that lagunamide A and B exhibit cytotoxicity by inducing mitochondria-mediated apoptosis [54].

Lagunamides
The cyclodepsipeptides lagunamide A (22) and B (23) were isolated from the filamentous marine cyanobacterium L. majuscule. These compounds were cytotoxic against P388 murine leukemia cell lines with IC50 values of 6.4-20.5 nM, respectively ( Figure 12) [54]. Furthermore, a biochemical analysis using HCT8 and MCF7 cancer cells indicated that lagunamide A and B exhibit cytotoxicity by inducing mitochondria-mediated apoptosis [54].

Lagunamides
The cyclodepsipeptides lagunamide A (22) and B (23) were isolated from the filamentous marine cyanobacterium L. majuscule. These compounds were cytotoxic against P388 murine leukemia cell lines with IC 50 values of 6.4-20.5 nM, respectively ( Figure 12) [54]. Furthermore, a biochemical analysis using HCT8 and MCF7 cancer cells indicated that lagunamide A and B exhibit cytotoxicity by inducing mitochondria-mediated apoptosis [54].
The mode of action of laxaphycin B (27) alone may be different from that of laxaphycin A in combination with laxaphycin B (26) [63]. Therefore, laxaphycins A and B could offer new visions into the clinical use of combinatorial drugs in the treatment of cancer.
The mode of action of laxaphycin B (27) alone may be different from that of laxaphycin A in combination with laxaphycin B (26) [63]. Therefore, laxaphycins A and B could offer new visions into the clinical use of combinatorial drugs in the treatment of cancer.
The mode of action of laxaphycin B (27) alone may be different from that of laxaphycin A in combination with laxaphycin B (26) [63]. Therefore, laxaphycins A and B could offer new visions into the clinical use of combinatorial drugs in the treatment of cancer.

Lyngbyastatin 4-7
Many cyclic depsipeptides isolated from marine cyanobacteria show strong inhibition of serine proteases such as pepsin, trypsin, α-chymotrypsin, and elastase. Serine protease is involved in a variety of disease states, including extermination of the extracellular surface of the cartilage covering
Lyngbyabellin B (30) showed effects on A10 human Burkitt lymphoma cells [64]. Furthermore, the cytotoxic effect of lyngbyabellin B was weaker than that of lyngbyabellin A against KB (IC50 values of 0.1 μg/mL) and LoVo (IC50 = 0.83 μg/mL) cells [64]. Many cyclic depsipeptides isolated from marine cyanobacteria show strong inhibition of serine proteases such as pepsin, trypsin, α-chymotrypsin, and elastase. Serine protease is involved in a variety of disease states, including extermination of the extracellular surface of the cartilage covering Many cyclic depsipeptides isolated from marine cyanobacteria show strong inhibition of serine proteases such as pepsin, trypsin, α-chymotrypsin, and elastase. Serine protease is involved in a variety of disease states, including extermination of the extracellular surface of the cartilage covering bones (articular cartilage) in arthritic refractory, emphysema, and inflammatory infections. For this reason, inhibition of serine proteases will be available as a new potential drug target for cancer therapy [66]. Lyngbyastatin 4-7 were depsipeptides isolated from Lyngbya (31-34) ( Figure 16) [67].

Fungi-Derived Peptides
Marine fungi produce biologically active and chemically solitary peptides that have offered research opportunities for effective cancer treatments. However, fungi-derived peptides, like sponge-derived peptides, are mostly secondary metabolites that are difficult to isolate. For this reason, the fungi-derived peptides are less studied than other marine peptides [11].

Fungi-Derived Peptides
Marine fungi produce biologically active and chemically solitary peptides that have offered research opportunities for effective cancer treatments. However, fungi-derived peptides, like sponge-derived peptides, are mostly secondary metabolites that are difficult to isolate. For this reason, the fungi-derived peptides are less studied than other marine peptides [11].

Fungi-Derived Peptides
Marine fungi produce biologically active and chemically solitary peptides that have offered research opportunities for effective cancer treatments. However, fungi-derived peptides, like spongederived peptides, are mostly secondary metabolites that are difficult to isolate. For this reason, the fungi-derived peptides are less studied than other marine peptides [11].

Sansalvamide A
The cyclic depsipeptide, Sansalvamide A (42), was isolated from Fusarium sp. living on the marine plant Halodule wrightii ( Figure 21) [75]. This peptide showed cytotoxicity against different cell lines such as pancreatic, colon, breast, prostate sarcoma and melanoma cancer cell lines, which suggests it is a potent chemotherapeutic agent (cytotoxicity against the HT29 cell was IC50 = 4.5 μg/mL) [76]. Until now, the exact mechanism of sansalvamide A is unknown. A recent research showed interaction between the HSP90 heat shock protein and client cancer proteins in mammalian cell lines. Sansalvamide A-amid is a synthetic peptide that has similar action to Sansalvamide A [76]. Sansalvamide A-amid was reported to bind to the N-middle domain of HSP90 and allosterically inhibits the formation of protein complex needed to promote tumor growth [76]. In addition, Sansalvamide A-amid caused G1 phase cell cycle arrest in the AsPC-1 and CD18 human pancreatic cancer cell lines. Ssansalvamide A acts as an inhibitor of topoisomerase I by inducing cell death by negligible apoptosis in several cancer cell lines [76].

Scopularide A and B
Scopularide A (43) and B (44) are cyclodepsipeptides isolated from the marine fungi Scopulariopsis brevicaulis and the marine sponge Tethya aurantium ( Figure 22) [77]. Both compounds have the ability to inhibit the growth of pancreatic and colon tumor cell lines [77]. These peptides have no antimicrobial activity against gram-negative bacteria and have weak activity against gram-positive bacteria [77]. However, the cytotoxicity of various tumor cell lines including the Colo357 and Panc89 pancreatic tumor cell lines and the HT29 colon tumor cell line was confirmed at the concentration of 10 μg/mL (IC50) [77].

Sansalvamide A
The cyclic depsipeptide, Sansalvamide A (42), was isolated from Fusarium sp. living on the marine plant Halodule wrightii ( Figure 21) [75]. This peptide showed cytotoxicity against different cell lines such as pancreatic, colon, breast, prostate sarcoma and melanoma cancer cell lines, which suggests it is a potent chemotherapeutic agent (cytotoxicity against the HT29 cell was IC 50 = 4.5 µg/mL) [76]. Until now, the exact mechanism of sansalvamide A is unknown. A recent research showed interaction between the HSP90 heat shock protein and client cancer proteins in mammalian cell lines. Sansalvamide A-amid is a synthetic peptide that has similar action to Sansalvamide A [76]. Sansalvamide A-amid was reported to bind to the N-middle domain of HSP90 and allosterically inhibits the formation of protein complex needed to promote tumor growth [76]. In addition, Sansalvamide A-amid caused G1 phase cell cycle arrest in the AsPC-1 and CD18 human pancreatic cancer cell lines. Ssansalvamide A acts as an inhibitor of topoisomerase I by inducing cell death by negligible apoptosis in several cancer cell lines [76].

Sansalvamide A
The cyclic depsipeptide, Sansalvamide A (42), was isolated from Fusarium sp. living on the marine plant Halodule wrightii (Figure 21) [75]. This peptide showed cytotoxicity against different cell lines such as pancreatic, colon, breast, prostate sarcoma and melanoma cancer cell lines, which suggests it is a potent chemotherapeutic agent (cytotoxicity against the HT29 cell was IC50 = 4.5 μg/mL) [76]. Until now, the exact mechanism of sansalvamide A is unknown. A recent research showed interaction between the HSP90 heat shock protein and client cancer proteins in mammalian cell lines. Sansalvamide A-amid is a synthetic peptide that has similar action to Sansalvamide A [76]. Sansalvamide A-amid was reported to bind to the N-middle domain of HSP90 and allosterically inhibits the formation of protein complex needed to promote tumor growth [76]. In addition, Sansalvamide A-amid caused G1 phase cell cycle arrest in the AsPC-1 and CD18 human pancreatic cancer cell lines. Ssansalvamide A acts as an inhibitor of topoisomerase I by inducing cell death by negligible apoptosis in several cancer cell lines [76].

Scopularide A and B
Scopularide A (43) and B (44) are cyclodepsipeptides isolated from the marine fungi Scopulariopsis brevicaulis and the marine sponge Tethya aurantium ( Figure 22) [77]. Both compounds have the ability to inhibit the growth of pancreatic and colon tumor cell lines [77]. These peptides have no antimicrobial activity against gram-negative bacteria and have weak activity against gram-positive bacteria [77]. However, the cytotoxicity of various tumor cell lines including the Colo357 and Panc89 pancreatic tumor cell lines and the HT29 colon tumor cell line was confirmed at the concentration of 10 μg/mL (IC50) [77].

Scopularide A and B
Scopularide A (43) and B (44) are cyclodepsipeptides isolated from the marine fungi Scopulariopsis brevicaulis and the marine sponge Tethya aurantium ( Figure 22) [77]. Both compounds have the ability to inhibit the growth of pancreatic and colon tumor cell lines [77]. These peptides have no antimicrobial activity against gram-negative bacteria and have weak activity against gram-positive bacteria [77]. However, the cytotoxicity of various tumor cell lines including the Colo357 and Panc89 pancreatic tumor cell lines and the HT29 colon tumor cell line was confirmed at the concentration of 10 µg/mL (IC 50 ) [77].

Sansalvamide A
The cyclic depsipeptide, Sansalvamide A (42), was isolated from Fusarium sp. living on the marine plant Halodule wrightii ( Figure 21) [75]. This peptide showed cytotoxicity against different cell lines such as pancreatic, colon, breast, prostate sarcoma and melanoma cancer cell lines, which suggests it is a potent chemotherapeutic agent (cytotoxicity against the HT29 cell was IC50 = 4.5 μg/mL) [76]. Until now, the exact mechanism of sansalvamide A is unknown. A recent research showed interaction between the HSP90 heat shock protein and client cancer proteins in mammalian cell lines. Sansalvamide A-amid is a synthetic peptide that has similar action to Sansalvamide A [76]. Sansalvamide A-amid was reported to bind to the N-middle domain of HSP90 and allosterically inhibits the formation of protein complex needed to promote tumor growth [76]. In addition, Sansalvamide A-amid caused G1 phase cell cycle arrest in the AsPC-1 and CD18 human pancreatic cancer cell lines. Ssansalvamide A acts as an inhibitor of topoisomerase I by inducing cell death by negligible apoptosis in several cancer cell lines [76].

Scopularide A and B
Scopularide A (43) and B (44) are cyclodepsipeptides isolated from the marine fungi Scopulariopsis brevicaulis and the marine sponge Tethya aurantium ( Figure 22) [77]. Both compounds have the ability to inhibit the growth of pancreatic and colon tumor cell lines [77]. These peptides have no antimicrobial activity against gram-negative bacteria and have weak activity against gram-positive bacteria [77]. However, the cytotoxicity of various tumor cell lines including the Colo357 and Panc89 pancreatic tumor cell lines and the HT29 colon tumor cell line was confirmed at the concentration of 10 μg/mL (IC50) [77].

Sponge-Derived Peptides
Anticancer peptides from sponges are mostly cyclodepsipeptides with unusual amino acids or non-amino acid parts. These sponge-derived peptides showed a broad range of anticancer or antitumor activity [78].

Arenastatin A
Arenastatin A (45), a macrocyclic depsipeptide, was isolated from Dysidea arenaria with extremely strong cytotoxic activity (IC 50 = 5 pg/mL) against a human nasopharyngeal carcinoma (KB) cell line ( Figure 23) [79]. Arenastatin A inhibits microtubule assembly due to the binding rhizoxin/maytansine sites of tubulin, resulting in cytotoxicity [80,81]. However, arenastatin A is unstable in mouse serum; there is little in vivo antitumor activity. The high sensitivity of the ester linkage to hydrolysis and degradation in blood is a disadvantage [82,83]. The synthesized 15-tert-butyl derivative of arenastatin A overcomes this disadvantage and exhibits improved serum stability as well as in vivo antitumor activity.

Sponge-Derived Peptides
Anticancer peptides from sponges are mostly cyclodepsipeptides with unusual amino acids or non-amino acid parts. These sponge-derived peptides showed a broad range of anticancer or antitumor activity [78].

Arenastatin A
Arenastatin A (45), a macrocyclic depsipeptide, was isolated from Dysidea arenaria with extremely strong cytotoxic activity (IC50 = 5 pg/mL) against a human nasopharyngeal carcinoma (KB) cell line (Figure 23) [79]. Arenastatin A inhibits microtubule assembly due to the binding rhizoxin/maytansine sites of tubulin, resulting in cytotoxicity [80,81]. However, arenastatin A is unstable in mouse serum; there is little in vivo antitumor activity. The high sensitivity of the ester linkage to hydrolysis and degradation in blood is a disadvantage [82,83]. The synthesized 15-tert-butyl derivative of arenastatin A overcomes this disadvantage and exhibits improved serum stability as well as in vivo antitumor activity.

Discodermin A-H
Discodermins are cytotoxic tetradecapeptides obtained from Discodermia sp. containing a macrocyclic ring formed by lactonization of a threonine amino acid unit at the C-terminal and 13-14 common and unusal amino acids-linked structures [84].

Discodermin A-H
Discodermins are cytotoxic tetradecapeptides obtained from Discodermia sp. containing a macrocyclic ring formed by lactonization of a threonine amino acid unit at the C-terminal and 13-14 common and unusal amino acids-linked structures [84].

Geodiamolide H
Geodiamolides were originally isolated from Geodia sp. as cyclic forms of peptides consisting of three amino acid residues with a common polyketide unit [85,86]. Geodiamolide H (54) is a cyclic depsipeptide isolated from G. corticostylifera, which showed in vitro cytotoxicity against several human cancer cell lines such as ovarian cancer, OV Car-4 (G 100 = 18.6 nM). Also, it has antiproliferative activity against the human breast cancer cells by altering the actin cytoskeleton ( Figure 25) [87].

Geodiamolide H
Geodiamolides were originally isolated from Geodia sp. as cyclic forms of peptides consisting of three amino acid residues with a common polyketide unit [85,86]. Geodiamolide H (54) is a cyclic depsipeptide isolated from G. corticostylifera, which showed in vitro cytotoxicity against several human cancer cell lines such as ovarian cancer, OV Car-4 (G100 = 18.6 nM). Also, it has antiproliferative activity against the human breast cancer cells by altering the actin cytoskeleton ( Figure 25) [87].
HT1286 (also called SPA-110 or taltobulin), a synthetic derivative of hemiasterlin, showed stronger cytotoxicity against human cancer cell lines than hemiasterlin, although both hemiasterlin and HT1286 have a similar mechanism of action. HT1286 has been shown to inhibit the growth of human tumor xenografts in mice, in a preclinical study [93]. The observed side effects, including alopecia, pain, and nausea, resulted in the cessation of HT1286 phase I clinical trials. However, HT1286 has high potential in the treatment of solid tumors in humans. Therefore, the development of new synthetic derivatives with fewer side effects is an important step toward the use of hemiasterlin as an anticancer drug [94,95].
HT1286 (also called SPA-110 or taltobulin), a synthetic derivative of hemiasterlin, showed stronger cytotoxicity against human cancer cell lines than hemiasterlin, although both hemiasterlin and HT1286 have a similar mechanism of action. HT1286 has been shown to inhibit the growth of human tumor xenografts in mice, in a preclinical study [93]. The observed side effects, including alopecia, pain, and nausea, resulted in the cessation of HT1286 phase I clinical trials. However, HT1286 has high potential in the treatment of solid tumors in humans. Therefore, the development of new synthetic derivatives with fewer side effects is an important step toward the use of hemiasterlin as an anticancer drug [94,95].

Geodiamolide H
Geodiamolides were originally isolated from Geodia sp. as cyclic forms of peptides consisting of three amino acid residues with a common polyketide unit [85,86]. Geodiamolide H (54) is a cyclic depsipeptide isolated from G. corticostylifera, which showed in vitro cytotoxicity against several human cancer cell lines such as ovarian cancer, OV Car-4 (G100 = 18.6 nM). Also, it has antiproliferative activity against the human breast cancer cells by altering the actin cytoskeleton ( Figure 25) [87].
HT1286 (also called SPA-110 or taltobulin), a synthetic derivative of hemiasterlin, showed stronger cytotoxicity against human cancer cell lines than hemiasterlin, although both hemiasterlin and HT1286 have a similar mechanism of action. HT1286 has been shown to inhibit the growth of human tumor xenografts in mice, in a preclinical study [93]. The observed side effects, including alopecia, pain, and nausea, resulted in the cessation of HT1286 phase I clinical trials. However, HT1286 has high potential in the treatment of solid tumors in humans. Therefore, the development of new synthetic derivatives with fewer side effects is an important step toward the use of hemiasterlin as an anticancer drug [94,95].
Jaspamide was found to be highly cytotoxic with an IC50 value of 0.04 ng/mL in P388 murine leukemia cells. It is a bioactive peptide that induces apoptosis in human leukemia cell lines and brain tumor Jurkat T cells by activation of caspase-3 protein expression and decrease in Bcl-2 levels [97][98][99].
In particular, transformed cell lines were more sensitive to jaspamide-induced cell death (apoptosis) than normal non-transformed cells [98].
Apoptosis induced by Jaspamide was associated with caspase-3 activation, decreased Bcl-2 protein expression, and increased Bax levels, suggesting that jaspamide induced a caspaseindependent cell death pathway for cytosolic and membrane changes in apoptosis cells, and a caspase-dependent cell death pathway for PARP protein degradation [99].
Jaspamide was found to be highly cytotoxic with an IC 50 value of 0.04 ng/mL in P388 murine leukemia cells. It is a bioactive peptide that induces apoptosis in human leukemia cell lines and brain tumor Jurkat T cells by activation of caspase-3 protein expression and decrease in Bcl-2 levels [97][98][99].
In particular, transformed cell lines were more sensitive to jaspamide-induced cell death (apoptosis) than normal non-transformed cells [98].
Apoptosis induced by Jaspamide was associated with caspase-3 activation, decreased Bcl-2 protein expression, and increased Bax levels, suggesting that jaspamide induced a caspase-independent cell death pathway for cytosolic and membrane changes in apoptosis cells, and a caspase-dependent cell death pathway for PARP protein degradation [99].
Jaspamide was found to be highly cytotoxic with an IC50 value of 0.04 ng/mL in P388 murine leukemia cells. It is a bioactive peptide that induces apoptosis in human leukemia cell lines and brain tumor Jurkat T cells by activation of caspase-3 protein expression and decrease in Bcl-2 levels [97][98][99].
In particular, transformed cell lines were more sensitive to jaspamide-induced cell death (apoptosis) than normal non-transformed cells [98].
Apoptosis induced by Jaspamide was associated with caspase-3 activation, decreased Bcl-2 protein expression, and increased Bax levels, suggesting that jaspamide induced a caspaseindependent cell death pathway for cytosolic and membrane changes in apoptosis cells, and a caspase-dependent cell death pathway for PARP protein degradation [99].

Koshikamide B and F-H
Koshikamide B (69) has been identified as the major cytotoxic constituent in two separate collections of the Theonella sp. Koshikamide B is a peptide lactone of 17-residue consisting of 6 proteinogenic amino acids, 2 D-isomers of proteinogenic amino acids, 2 unusual amino acids, and 7 N-methylated amino acids ( Figure 29) [100]. It was confirmed that the IC 50 values for human leukemia cells (P388) and human colon tumor (HCT-116) cell lines were 0.22 and 3.7 µM, respectively [100].
Koshikamide F-H (70-72) are 17-residue depsipeptides with macrolactone, their IC 50 values were inhibited entry from 2.3 to 5.5 µM. (Figure 29) [101]. Koshikamide H (72) was found to have moderate cytotoxicity against the HCT-116 colon cancer cell line with IC 50 value of 10 µM. However, koshikamides F-H did not inhibit the growth of Candida albicans, indicating that it is cytotoxic without antifungal activity [101].  (69) has been identified as the major cytotoxic constituent in two separate collections of the Theonella sp. Koshikamide B is a peptide lactone of 17-residue consisting of 6 proteinogenic amino acids, 2 D-isomers of proteinogenic amino acids, 2 unusual amino acids, and 7 N-methylated amino acids ( Figure 29) [100]. It was confirmed that the IC50 values for human leukemia cells (P388) and human colon tumor (HCT-116) cell lines were 0.22 and 3.7 μM, respectively [100].

Koshikamide B and F-H
Koshikamide B (69) has been identified as the major cytotoxic constituent in two separate collections of the Theonella sp. Koshikamide B is a peptide lactone of 17-residue consisting of 6 proteinogenic amino acids, 2 D-isomers of proteinogenic amino acids, 2 unusual amino acids, and 7 N-methylated amino acids (Figure 29) [100]. It was confirmed that the IC50 values for human leukemia cells (P388) and human colon tumor (HCT-116) cell lines were 0.22 and 3.7 μM, respectively [100].

Phakellistatins
Proline rich-cyclic heptapeptides, Phakellistatins, are isolated from Phakellia carteri and these compounds inhibit leukemia cell growth ( Figure 33) [106]. Phakellistatin 1 (82) significantly inhibited growth of the P388 lymphocytic leukemia (50% effective dose, ED50 = 7.5 μg/mL) and other different melanoma cell lines [107]. Phakellistatin 13 (83) isolated from Phakellia fusca showed cytotoxicity against the BEL-7404 human hepatoma cell line (IC50 < 10 ng/mL). When synthetic phakellistatins were tested, they were inactive, unlike natural products. This may be explained by conformational differences, especially around the proline residue [108]. In other words, the biological properties of synthetic products were found to be significantly different from the products isolated from nature.

Phakellistatins
Proline rich-cyclic heptapeptides, Phakellistatins, are isolated from Phakellia carteri and these compounds inhibit leukemia cell growth ( Figure 33) [106]. Phakellistatin 1 (82) significantly inhibited growth of the P388 lymphocytic leukemia (50% effective dose, ED50 = 7.5 μg/mL) and other different melanoma cell lines [107]. Phakellistatin 13 (83) isolated from Phakellia fusca showed cytotoxicity against the BEL-7404 human hepatoma cell line (IC50 < 10 ng/mL). When synthetic phakellistatins were tested, they were inactive, unlike natural products. This may be explained by conformational differences, especially around the proline residue [108]. In other words, the biological properties of synthetic products were found to be significantly different from the products isolated from nature.

Phakellistatins
Proline rich-cyclic heptapeptides, Phakellistatins, are isolated from Phakellia carteri and these compounds inhibit leukemia cell growth ( Figure 33) [106]. Phakellistatin 1 (82) significantly inhibited growth of the P388 lymphocytic leukemia (50% effective dose, ED 50 = 7.5 µg/mL) and other different melanoma cell lines [107]. Phakellistatin 13 (83) isolated from Phakellia fusca showed cytotoxicity against the BEL-7404 human hepatoma cell line (IC 50 < 10 ng/mL). When synthetic phakellistatins were tested, they were inactive, unlike natural products. This may be explained by conformational differences, especially around the proline residue [108]. In other words, the biological properties of synthetic products were found to be significantly different from the products isolated from nature.   [110,111]. Scleritodermin A has a structure that combines the keto-Ile-Pro-Ser-Pro-SerOMe portion and the conjugated thiazole moiety. Scleritodermin A (85) has been observed to potently inhibit tubulin polymerization in different cancer cells because of the cell cycle arrest in the G2/M phase [110,111].    [110,111]. Scleritodermin A has a structure that combines the keto-Ile-Pro-Ser-Pro-SerOMe portion and the conjugated thiazole moiety. Scleritodermin A (85) has been observed to potently inhibit tubulin polymerization in different cancer cells because of the cell cycle arrest in the G2/M phase [110,111].   [110,111]. Scleritodermin A has a structure that combines the keto-Ile-Pro-Ser-Pro-SerOMe portion and the conjugated thiazole moiety. Scleritodermin A (85) has been observed to potently inhibit tubulin polymerization in different cancer cells because of the cell cycle arrest in the G2/M phase [110,111].   [110,111]. Scleritodermin A has a structure that combines the keto-Ile-Pro-Ser-Pro-SerOMe portion and the conjugated thiazole moiety. Scleritodermin A (85) has been observed to potently inhibit tubulin polymerization in different cancer cells because of the cell cycle arrest in the G2/M phase [110,111].

Tunicate and Ascidia-Derived Peptides
Marine tunicates and ascidiae produce many biologically active peptides; they produce more antitumor and anticancer peptides than any other group of marine organisms [7,11].
The mechanism of action of aplidin involves cell cycle arrest at the G1-G2 phase, inhibition of protein synthesis, and induction of cancer cell death through induction of apoptosis [115]. Aplidin (86) induced early oxidative stress and then, the activation of both JNK and p38 mitogen-activated protein kinases (MAPK) occurred rapidly and steadily. Phosphorylation by the activation of both kinases occurred rapidly and fully in the drug treatment of HeLa human tumor cells. Activation of JNK and p38 MAPK resulted in downstream of cytochrome c release, upstream of caspase-9 and caspase-3 activation, and PARP cleavage, indicating the strong suppressor of the mitochondrial apoptosis pathway [115,116]. The two mechanisms (apoptosis via caspase-dependent and -independent mechanisms) by which aplidin activated JNK are rapid induction of Rac1 small GTPase and downregulation of MKP-1 phosphatase. Furthermore, aplidin induced other kinases such as the epidermal growth factor receptor (EGFR), the non-receptor protein-tyrosine kinase Src, and the serine/threonine kinases JNK and p38 MAPK in the MDA-MB-231 breast cancer cells.
The availability of the natural marine resource of aplidin is limited due to the difficulty of collecting A. albicans. The limited availability has led to the development of the synthetic analogues.
Aplidin also inhibited the expression of the vascular endothelial growth factor gene, resulting in biological effects such as angiogenesis, hematopoiesis, and vascular homeostasis [121]. However, aplidin was more effective than didemnin B in preclinical models and, to date, there is no evidence of toxicity to life-threatening neuromuscular disease [112,115].

Tunicate and Ascidia-Derived Peptides
Marine tunicates and ascidiae produce many biologically active peptides; they produce more antitumor and anticancer peptides than any other group of marine organisms [7,11].
The mechanism of action of aplidin involves cell cycle arrest at the G1-G2 phase, inhibition of protein synthesis, and induction of cancer cell death through induction of apoptosis [115]. Aplidin (86) induced early oxidative stress and then, the activation of both JNK and p38 mitogen-activated protein kinases (MAPK) occurred rapidly and steadily. Phosphorylation by the activation of both kinases occurred rapidly and fully in the drug treatment of HeLa human tumor cells. Activation of JNK and p38 MAPK resulted in downstream of cytochrome c release, upstream of caspase-9 and caspase-3 activation, and PARP cleavage, indicating the strong suppressor of the mitochondrial apoptosis pathway [115,116]. The two mechanisms (apoptosis via caspase-dependent and -independent mechanisms) by which aplidin activated JNK are rapid induction of Rac1 small GTPase and downregulation of MKP-1 phosphatase. Furthermore, aplidin induced other kinases such as the epidermal growth factor receptor (EGFR), the non-receptor protein-tyrosine kinase Src, and the serine/threonine kinases JNK and p38 MAPK in the MDA-MB-231 breast cancer cells.
The availability of the natural marine resource of aplidin is limited due to the difficulty of collecting A. albicans. The limited availability has led to the development of the synthetic analogues.
Aplidin also inhibited the expression of the vascular endothelial growth factor gene, resulting in biological effects such as angiogenesis, hematopoiesis, and vascular homeostasis [121]. However, aplidin was more effective than didemnin B in preclinical models and, to date, there is no evidence of toxicity to life-threatening neuromuscular disease [112,115].

Didemnin B
Some peptides derived from natural marine resource are shown to induce apoptosis through various mechanisms including cell membrane blebbing, nuclear condensation, and DNA fragmentation. However, the actual mechanism of action for this cytotoxic activity is still unclear. The cycle depsipeptides didemnins were first isolated from Trididemnum solidum, which showed strong antitumor, immunosuppressive, and antiviral properties [8,83].
Didemnin B (87) showed the highest anticancer activity against human prostatic cancer cell lines (IC50 = 2 ng/mL in L1210 leukemia cell) and antiproliferative activity against P388 leukemia as

Didemnin B
Some peptides derived from natural marine resource are shown to induce apoptosis through various mechanisms including cell membrane blebbing, nuclear condensation, and DNA fragmentation. However, the actual mechanism of action for this cytotoxic activity is still unclear. The cycle depsipeptides didemnins were first isolated from Trididemnum solidum, which showed strong antitumor, immunosuppressive, and antiviral properties [8,83].
Didemnin B (87) showed the highest anticancer activity against human prostatic cancer cell lines (IC 50 = 2 ng/mL in L1210 leukemia cell) and antiproliferative activity against P388 leukemia as well as B16 melanoma (Figure 37) [83]. For this reason, didemnin B (87) became the first ascidiacea cytotoxin to enter into clinical trials as a potent anticancer drug [122].
Didemnin B has shown impressive anti-cancer activity via the inhibition of protein synthesis [123]. Didemnin B has been approved for clinical use as an anticancer agent, but its use is limited due to toxicity and lack of efficacy during a phase II study and an unclear mechanism of action [124]. Furthermore, its low solubility and a short lifespan led to the termination of didemnin B phase II clinical trials [122]. Dehydrodidemnin B (aplidin), an oxidative derivatve of didemnin B, was isolated from A. albicans and exhibits more potent anticancer activity than didermin B [25]. Currently dehydrodidemnin B is in phase II clinical trials in the USA and Europe [25]. well as B16 melanoma ( Figure 37) [83]. For this reason, didemnin B (87) became the first ascidiacea cytotoxin to enter into clinical trials as a potent anticancer drug [122]. Didemnin B has shown impressive anti-cancer activity via the inhibition of protein synthesis [123]. Didemnin B has been approved for clinical use as an anticancer agent, but its use is limited due to toxicity and lack of efficacy during a phase II study and an unclear mechanism of action [124]. Furthermore, its low solubility and a short lifespan led to the termination of didemnin B phase II clinical trials [122]. Dehydrodidemnin B (aplidin), an oxidative derivatve of didemnin B, was isolated from A. albicans and exhibits more potent anticancer activity than didermin B [25]. Currently dehydrodidemnin B is in phase II clinical trials in the USA and Europe [25].

Cycloxazoline
Cycloxazoline (88), a cyclic hexapeptide found from Lissoclinum bistratum, showed potent anti-apoptotic activity in various cancer cell lines but the exact target is presently unknown ( Figure  38) [124,125]. The compound displayed cytotoxicity against MRC5CV1 and T24 cells (IC50 = 0.5 μg/mL). Cycloxazoline caused accumulation of HL-60 leukemia cells in the G2/M phase and interference with cytokinesis by phosphorylation of cellular proteins involved in cell-cycle control [125].

Diazonamide A
Diazonamide A (89), a complex cytotoxic peptide was isolated from Diazona angulate, and displayed potent inhibition of tubulin polymerization in several cancer cells ( Figure 39) [126,127]. It showed strong antitumor activity with an IC50 value of 2-5 nM against four human cancer cell lines (CA46, MCF7, PC-3, and A549). Furthermore, diazonamide A has a unique binding site for tubulin that differs from the vinca alkaloid or dolastatin 10 binding sites. So, it weakly inhibits the polymerization of tubulin into strong microtubules ends [126,127].

Cycloxazoline
Cycloxazoline (88), a cyclic hexapeptide found from Lissoclinum bistratum, showed potent anti-apoptotic activity in various cancer cell lines but the exact target is presently unknown (Figure 38) [124,125]. The compound displayed cytotoxicity against MRC5CV1 and T24 cells (IC 50 = 0.5 µg/mL). Cycloxazoline caused accumulation of HL-60 leukemia cells in the G2/M phase and interference with cytokinesis by phosphorylation of cellular proteins involved in cell-cycle control [125]. well as B16 melanoma ( Figure 37) [83]. For this reason, didemnin B (87) became the first ascidiacea cytotoxin to enter into clinical trials as a potent anticancer drug [122]. Didemnin B has shown impressive anti-cancer activity via the inhibition of protein synthesis [123]. Didemnin B has been approved for clinical use as an anticancer agent, but its use is limited due to toxicity and lack of efficacy during a phase II study and an unclear mechanism of action [124]. Furthermore, its low solubility and a short lifespan led to the termination of didemnin B phase II clinical trials [122]. Dehydrodidemnin B (aplidin), an oxidative derivatve of didemnin B, was isolated from A. albicans and exhibits more potent anticancer activity than didermin B [25]. Currently dehydrodidemnin B is in phase II clinical trials in the USA and Europe [25].

Cycloxazoline
Cycloxazoline (88), a cyclic hexapeptide found from Lissoclinum bistratum, showed potent anti-apoptotic activity in various cancer cell lines but the exact target is presently unknown ( Figure  38) [124,125]. The compound displayed cytotoxicity against MRC5CV1 and T24 cells (IC50 = 0.5 μg/mL). Cycloxazoline caused accumulation of HL-60 leukemia cells in the G2/M phase and interference with cytokinesis by phosphorylation of cellular proteins involved in cell-cycle control [125].

Diazonamide A
Diazonamide A (89), a complex cytotoxic peptide was isolated from Diazona angulate, and displayed potent inhibition of tubulin polymerization in several cancer cells ( Figure 39) [126,127]. It showed strong antitumor activity with an IC50 value of 2-5 nM against four human cancer cell lines (CA46, MCF7, PC-3, and A549). Furthermore, diazonamide A has a unique binding site for tubulin that differs from the vinca alkaloid or dolastatin 10 binding sites. So, it weakly inhibits the polymerization of tubulin into strong microtubules ends [126,127].

Diazonamide A
Diazonamide A (89), a complex cytotoxic peptide was isolated from Diazona angulate, and displayed potent inhibition of tubulin polymerization in several cancer cells ( Figure 39) [126,127]. It showed strong antitumor activity with an IC 50 value of 2-5 nM against four human cancer cell lines (CA46, MCF7, PC-3, and A549). Furthermore, diazonamide A has a unique binding site for tubulin that differs from the vinca alkaloid or dolastatin 10 binding sites. So, it weakly inhibits the polymerization of tubulin into strong microtubules ends [126,127].

Mollamide B and C
Mollamide from Didemnum molle was cyclodepsipeptide and showed cytotoxicity in P388 murine leukemia cells (IC50 values of 1 μg/mL) and in A549 human lung carcinoma and HT29 human colon carcinoma cells (2.5 μg/mL) ( Figure 40) [128,129]. Among these, mollamide B (90) showed significant percent growth inhibition at 100 μM in the H460 non-small cell lung cancer cell, MCF7 breast cancer cell, and SF-268 CNS cancer cell line, but the National Cancer Institute (NCI) 60-cell line panel lacked tumor cell selectivity [130]. In contrast to mollamide B, mollamide C (91) showed strong in vitro cytotoxicity against leukemias (L1210 and CCRF-CEM), solid tumors (38, HCT-116, H125, MCF-7, and LNCaP), and a human normal cell (hematopoietic progenitor cell, CFU-GM); this was observed using a disk diffusion assay. The results showed that the leukemia and normal cells were slightly toxic but showed a larger difference in the solid tumor group [130].

Mollamide B and C
Mollamide from Didemnum molle was cyclodepsipeptide and showed cytotoxicity in P388 murine leukemia cells (IC 50 values of 1 µg/mL) and in A549 human lung carcinoma and HT29 human colon carcinoma cells (2.5 µg/mL) ( Figure 40) [128,129]. Among these, mollamide B (90) showed significant percent growth inhibition at 100 µM in the H460 non-small cell lung cancer cell, MCF7 breast cancer cell, and SF-268 CNS cancer cell line, but the National Cancer Institute (NCI) 60-cell line panel lacked tumor cell selectivity [130]. In contrast to mollamide B, mollamide C (91) showed strong in vitro cytotoxicity against leukemias (L1210 and CCRF-CEM), solid tumors (38, HCT-116, H125, MCF-7, and LNCaP), and a human normal cell (hematopoietic progenitor cell, CFU-GM); this was observed using a disk diffusion assay. The results showed that the leukemia and normal cells were slightly toxic but showed a larger difference in the solid tumor group [130].

Mollamide B and C
Mollamide from Didemnum molle was cyclodepsipeptide and showed cytotoxicity in P388 murine leukemia cells (IC50 values of 1 μg/mL) and in A549 human lung carcinoma and HT29 human colon carcinoma cells (2.5 μg/mL) ( Figure 40) [128,129]. Among these, mollamide B (90) showed significant percent growth inhibition at 100 μM in the H460 non-small cell lung cancer cell, MCF7 breast cancer cell, and SF-268 CNS cancer cell line, but the National Cancer Institute (NCI) 60-cell line panel lacked tumor cell selectivity [130]. In contrast to mollamide B, mollamide C (91) showed strong in vitro cytotoxicity against leukemias (L1210 and CCRF-CEM), solid tumors (38, HCT-116, H125, MCF-7, and LNCaP), and a human normal cell (hematopoietic progenitor cell, CFU-GM); this was observed using a disk diffusion assay. The results showed that the leukemia and normal cells were slightly toxic but showed a larger difference in the solid tumor group [130].

Tamandarin A and B
Tamandarin A (92) and B (93) are cyclodepsipeptides associated with didemnins known as highly active antiviral, antitumor, and immunosuppressive peptides [131]. Tamandarin A (92) and B (93) were isolated from Trididemnum solidum, Trididemnum cyanophorum, Aplidium albicans, and an unidentified ascidian (family Didemnidae) ( Figure 41) [131]. Tamandarin A (92) and B (93) showed strong cytotoxicity against human cancer cell lines, and appeared to be a more potent inhibitor of protein synthesis in comparison with dedermin B [131]. However, their molecular mechanism of action is still unclear. Tamandarin A (92) was found to show cytotoxic activity on three cell lines, BX-PC3 pancreatic carcinoma, DU145 carcinoma, and UMSCC10b head and neck carcinoma with IC 50 values of 1.79, 1.36, and 0.99 ng/mL, respectively [131].
The colchicine binding to tubulin was tested at concentrations up to 80 µM, and was found to be stabilized in the presence of vitilevuamide. It has also been shown to be weakly affected by the presence of GTP-binding in the presence of vitilevuamide, suggesting that vitilevuamide may inhibit tubulin polymerization through interaction at a unique site [134].
Vitilevuamide inhibited the growth of various human cancer cell lines with IC 50 values in the range of 6-311 nM, confirming that they were associated with G 2 /M cell cycle arrest. In mice implanted with P388 lymphocytic leukemia, the intraperitoneal administration of vitilevuamide at doses of 12-30 mg/kg on days 1.5 and 9 after administration resulted in increased life span [122,134].  (98), a bicyclic depsipeptide isolated from Didemnum cuculiferum and Polysyncranton lithostrotum, is a tubulin-interactive agent, and potentially positive in a cell-based screening for tubulin polymerization inhibitors of purified tubulin (IC50 = 2.5 μM) (Figure 44) [134]. This demonstrates that vitilevuamide (98) showed non-competitive inhibition of vinblastine binding to tubulin.
The colchicine binding to tubulin was tested at concentrations up to 80 μM, and was found to be stabilized in the presence of vitilevuamide. It has also been shown to be weakly affected by the presence of GTP-binding in the presence of vitilevuamide, suggesting that vitilevuamide may inhibit tubulin polymerization through interaction at a unique site [134].
Vitilevuamide inhibited the growth of various human cancer cell lines with IC50 values in the range of 6-311 nM, confirming that they were associated with G2/M cell cycle arrest. In mice implanted with P388 lymphocytic leukemia, the intraperitoneal administration of vitilevuamide at doses of 12-30 mg/kg on days 1.5 and 9 after administration resulted in increased life span [122,134].

Mollusk and Fish-Derived Anticancer Peptides
Marine mollusks and fish-derived peptides are pharmacologically active products and often have activity in cancerous tumors. For this reason, many research groups have been interested in identifying anticancer peptides from fish for many years. However, there are few reports of marine mollusks and fish-derived anticancer peptides compared to other marine resources. Therefore, further research is needed to develop mollusks and fish-derived anticancer peptide and other physiologically active peptides, and it is expected to be a biomass in the future.

Dolastatins
Dolastatins are cytotoxic linear or cyclic peptides isolated from Dolabella auricularia, among the dolastatins, dolastatin 10 (99) and 15 (100) showed the most promising antiproliferative action ( Figure 45) [135]. Dolastatin 10 is a linear pentapeptide that contains several unique amino acid residues and is the most potent antiproliferative dolastatin. It inhibited the cell growth of L1210 murine leukemia (IC50 = 0.5 nM) and human bucket lymphoma CA46 cells (IC50 = 50 pM). For this reason, dolastatin 10 (99) has been selected for clinical trials because of its favorable preclinical advantage and is currently on clinical trials in Phase I as an anticancer drug [136].
The depsipeptide dolastatin 15 (100) inhibited the growth of L1210 cells (IC50 = 3 nM) and CA46 cells (IC50 = 5 nM) [137]. Dolastatin 10 was also extremely potent in vitro. Microtubule assembly and tubulin polymerization were inhibited, causing the accumulation of cells that were arrested in metaphase [138,139]. Dolastatin 10 is a promising candidate with an antineoplastic profile against various cancer cell lines. It has been investigated in various phase I clinical studies, which reported good tolerability and identified bone marrow depression as dose-limiting toxicity. However,

Mollusk and Fish-Derived Anticancer Peptides
Marine mollusks and fish-derived peptides are pharmacologically active products and often have activity in cancerous tumors. For this reason, many research groups have been interested in identifying anticancer peptides from fish for many years. However, there are few reports of marine mollusks and fish-derived anticancer peptides compared to other marine resources. Therefore, further research is needed to develop mollusks and fish-derived anticancer peptide and other physiologically active peptides, and it is expected to be a biomass in the future.

Dolastatins
Dolastatins are cytotoxic linear or cyclic peptides isolated from Dolabella auricularia, among the dolastatins, dolastatin 10 (99) and 15 (100) showed the most promising antiproliferative action ( Figure 45) [135]. Dolastatin 10 is a linear pentapeptide that contains several unique amino acid residues and is the most potent antiproliferative dolastatin. It inhibited the cell growth of L1210 murine leukemia (IC 50 = 0.5 nM) and human bucket lymphoma CA46 cells (IC 50 = 50 pM). For this reason, dolastatin 10 (99) has been selected for clinical trials because of its favorable preclinical advantage and is currently on clinical trials in Phase I as an anticancer drug [136].
The depsipeptide dolastatin 15 (100) inhibited the growth of L1210 cells (IC 50 = 3 nM) and CA46 cells (IC 50 = 5 nM) [137]. Dolastatin 10 was also extremely potent in vitro. Microtubule assembly and tubulin polymerization were inhibited, causing the accumulation of cells that were arrested in metaphase [138,139]. Dolastatin 10 is a promising candidate with an antineoplastic profile against various cancer cell lines. It has been investigated in various phase I clinical studies, which reported good tolerability and identified bone marrow depression as dose-limiting toxicity. However, dolastatin 10 has been found to cause myelosuppression, peripheral sensory neuropathy, and local irritation at the drug injection site. Structural complexity, low synthetic yield and low water solubility of dolastatins are critical barriers to their broadly clinical evaluation as anticancer drugs [137].
Based on the structural model of dolastatin 10, various analogs were synthesized. Among these analogs, TZT-1027 is a drug with antivascular activity that depolarizes microtubules and disrupts newly formed tumor vasculature. TZT-1027 was found to possess antiangiogenic activity in chorioallantoic membrane embryo (CAM) and human umbilical vein endothelial cells (HUVECs) in vivo [140]. However, it did not show anticancer activity in a phase II clinical trials in patients with advanced non-small cell lung cancer treated with platinum-based chemotherapy [141].
Dolastatin 15 (100) isolated from D. auricularia has not yet been clinically studied, but water-soluble derivates LU-103793 (cematodin) and ILX651 (synthadotin) were developed as cancer drug candidates for clinical studies. LU-103793 was successful in a phase I clinical trial for the treatment of several cancers. The phase II trial was interrupted by unexpected research results. ILX-651 successfully completed the phase I clinical trial and a phase II trial has been recommended owing to its good tolerability with no cardiotoxicities, unlike LU-103793. ILX651 has finished at the least three rounds of phase II clinical trials in patients with advanced and/or metastatic hormone-refractory prostate cancer [29]. dolastatin 10 has been found to cause myelosuppression, peripheral sensory neuropathy, and local irritation at the drug injection site. Structural complexity, low synthetic yield and low water solubility of dolastatins are critical barriers to their broadly clinical evaluation as anticancer drugs [137].
Based on the structural model of dolastatin 10, various analogs were synthesized. Among these analogs, TZT-1027 is a drug with antivascular activity that depolarizes microtubules and disrupts newly formed tumor vasculature. TZT-1027 was found to possess antiangiogenic activity in chorioallantoic membrane embryo (CAM) and human umbilical vein endothelial cells (HUVECs) in vivo [140]. However, it did not show anticancer activity in a phase II clinical trials in patients with advanced non-small cell lung cancer treated with platinum-based chemotherapy [141].
Dolastatin 15 (100) isolated from D. auricularia has not yet been clinically studied, but water-soluble derivates LU-103793 (cematodin) and ILX651 (synthadotin) were developed as cancer drug candidates for clinical studies. LU-103793 was successful in a phase I clinical trial for the treatment of several cancers. The phase II trial was interrupted by unexpected research results. ILX-651 successfully completed the phase I clinical trial and a phase II trial has been recommended owing to its good tolerability with no cardiotoxicities, unlike LU-103793. ILX651 has finished at the least three rounds of phase II clinical trials in patients with advanced and/or metastatic hormone-refractory prostate cancer [29].
A synthetic cyclic depsipeptide kahalalide F derivative, elisidepsin (PM02734, also known as Irvalec ® ) has potential antineoplastic activity similar to kahalalide F. Elisidepsin shows anti-proliferative activity in a broad variety of cancer cell types [151][152][153]. The action of elisidepsin appears to be as a result of the induction of oncolysis rather than cell death by apoptosis in cancer cells. Elisidepsin is also in phase II clinical trials on metastatic or advanced gastroesophageal cancer [154]. These results were promising and presented a rational basis for further investigations and clinical trials for cancer treatment [155].
A synthetic cyclic depsipeptide kahalalide F derivative, elisidepsin (PM02734, also known as Irvalec ® ) has potential antineoplastic activity similar to kahalalide F. Elisidepsin shows anti-proliferative activity in a broad variety of cancer cell types [151][152][153]. The action of elisidepsin appears to be as a result of the induction of oncolysis rather than cell death by apoptosis in cancer cells. Elisidepsin is also in phase II clinical trials on metastatic or advanced gastroesophageal cancer [154]. These results were promising and presented a rational basis for further investigations and clinical trials for cancer treatment [155].

Ziconotide
Ziconotide (104) present in the venom of Conus magus, has a structure in which 25 amino acid peptides linked by three disulfide bonds ( Figure 49) [158]. Ziconotide has been developed as an

Ziconotide
Ziconotide (104) present in the venom of Conus magus, has a structure in which 25 amino acid peptides linked by three disulfide bonds ( Figure 49) [158]. Ziconotide has been developed as an

Ziconotide
Ziconotide (104) present in the venom of Conus magus, has a structure in which 25 amino acid peptides linked by three disulfide bonds ( Figure 49) [158]. Ziconotide has been developed as an

Ziconotide
Ziconotide (104) present in the venom of Conus magus, has a structure in which 25 amino acid peptides linked by three disulfide bonds ( Figure 49) [158]. Ziconotide has been developed as an atypical analgesic to relieve severe and chronic pain by acting as an optional N-type voltage gated calcium channel blocker. This action has been shown to relieve pain by inhibiting the release of glutamate, calcitonin gene related peptide and pro-invasive neurochemicals such as substance P in the brain and spinal cord [158,159].
It has been shown to have a 1000-fold higher activity than morphine in animal models of nociceptive pain and has a remarkable analgesic character [158]. Ziconotide (trade name Prialt ® ) was the first marine peptide to receive FDA approval for analgesic use in 2004 and another marine peptide Brentuximab vedotin (trade name Adcetris ® ) was approved by the FDA in 2011 for drugs that are effective against cancer [159,160]. Various marine peptides are now entering phases of clinical trials in the United States and Europe [161]. atypical analgesic to relieve severe and chronic pain by acting as an optional N-type voltage gated calcium channel blocker. This action has been shown to relieve pain by inhibiting the release of glutamate, calcitonin gene related peptide and pro-invasive neurochemicals such as substance P in the brain and spinal cord [158,159]. It has been shown to have a 1000-fold higher activity than morphine in animal models of nociceptive pain and has a remarkable analgesic character [158]. Ziconotide (trade name Prialt ® ) was the first marine peptide to receive FDA approval for analgesic use in 2004 and another marine peptide Brentuximab vedotin (trade name Adcetris ® ) was approved by the FDA in 2011 for drugs that are effective against cancer [159,160]. Various marine peptides are now entering phases of clinical trials in the United States and Europe [161].  [158]. Ziconotide has six cysteine residues, forming three disulfide bonds.

Pardaxin
Pardaxin (105, GFFALIPKIISSPLFKTLLSAVGSALSSSGGQE-NH2) is an antimicrobial peptide consisting of 33 amino acids, isolated from the fish Pardachirus marmoratus [77]. This peptide showed antitumor activity in human fibrosarcoma (HT1080) cells and HeLa cells, which inhibited proliferation in a dose-dependent manner in HT1080 cells and induced programmed cell death in HeLa cells [77]. In HT1080 cells, pardaxin induced apoptosis by causing caspase-dependent and ROS-mediated cell death [162].
Pardaxin plays important roles in the scavenging of reactive oxygen species (ROS) to alleviate c-Jun activation. Small interfering RNA-mediated knockdown of c-Jun requiring ROS and c-Jun in pardaxin-induced apoptosis signaling as it abrogates pardaxin-induced caspase activation and cell death [162].
Pardaxin, unlike HT1080 cells, causes caspase-dependent and caspase-independent apoptosis in human cervical cancer cells. Pardaxin also induces >90% inhibition of colony formation in MN-11 cells derived from MC1A fibrosarcoma in male C57BL/10 mice at a concentration of 13 μg/mL [163]. In addition, pardaxin has a potential veterinary application because it has a lytic action with potent activity against canine perianal gland adenomas [163].

YALRAH
Tyr-Ala-Leu-Pro-Ala-His (106), an anticancer peptide consisting of six residues derived from the half-fin anchovy (Setipinna taty), has been shown to inhibit the proliferation of prostate cancer cells [164]. YALPAH and three analogs (YALRAH, YALPAR and YALPAG) exhibited anti-proliferative activity in PC3 cells. Among them, the modified peptide YALRAH showed the strongest activity (IC50 value of 11.1 μM). It has been confirmed that arginine (R) is an important residue for anticancer activity, but the mechanism for this is still unclear [164].

Anticancer Peptide-Based Drug Therapeutics Developed from Marine Organisms and Future Prospects
Many factors are involved in the discovery and development of anticancer drugs from marine natural products. However, there are various reasons that have ensured the use of marine peptides in the search for anticancer drugs. Marine-derived peptides are chemically diverse, have a wide range of therapeutic activities, and are highly specific to cells or tissues. These peptides can act specifically against cancer cells by either membranolytic mechanisms or mitochondrial disruption [165]. Generally, the negative net charge of the cancer membrane is an important factor for peptide selectivity and toxicity, especially relative to the typically zwitterionic properties of normal cell Figure 49. Primary structure of ziconotide (104) [158]. Ziconotide has six cysteine residues, forming three disulfide bonds.

Pardaxin
Pardaxin (105, GFFALIPKIISSPLFKTLLSAVGSALSSSGGQE-NH 2 ) is an antimicrobial peptide consisting of 33 amino acids, isolated from the fish Pardachirus marmoratus [77]. This peptide showed antitumor activity in human fibrosarcoma (HT1080) cells and HeLa cells, which inhibited proliferation in a dose-dependent manner in HT1080 cells and induced programmed cell death in HeLa cells [77]. In HT1080 cells, pardaxin induced apoptosis by causing caspase-dependent and ROS-mediated cell death [162].
Pardaxin plays important roles in the scavenging of reactive oxygen species (ROS) to alleviate c-Jun activation. Small interfering RNA-mediated knockdown of c-Jun requiring ROS and c-Jun in pardaxin-induced apoptosis signaling as it abrogates pardaxin-induced caspase activation and cell death [162].
Pardaxin, unlike HT1080 cells, causes caspase-dependent and caspase-independent apoptosis in human cervical cancer cells. Pardaxin also induces >90% inhibition of colony formation in MN-11 cells derived from MC1A fibrosarcoma in male C57BL/10 mice at a concentration of 13 µg/mL [163]. In addition, pardaxin has a potential veterinary application because it has a lytic action with potent activity against canine perianal gland adenomas [163].

YALRAH
Tyr-Ala-Leu-Pro-Ala-His (106), an anticancer peptide consisting of six residues derived from the half-fin anchovy (Setipinna taty), has been shown to inhibit the proliferation of prostate cancer cells [164]. YALPAH and three analogs (YALRAH, YALPAR and YALPAG) exhibited anti-proliferative activity in PC3 cells. Among them, the modified peptide YALRAH showed the strongest activity (IC 50 value of 11.1 µM). It has been confirmed that arginine (R) is an important residue for anticancer activity, but the mechanism for this is still unclear [164].

Anticancer Peptide-Based Drug Therapeutics Developed from Marine Organisms and Future Prospects
Many factors are involved in the discovery and development of anticancer drugs from marine natural products. However, there are various reasons that have ensured the use of marine peptides in the search for anticancer drugs. Marine-derived peptides are chemically diverse, have a wide range of therapeutic activities, and are highly specific to cells or tissues. These peptides can act specifically against cancer cells by either membranolytic mechanisms or mitochondrial disruption [165]. Generally, the negative net charge of the cancer membrane is an important factor for peptide selectivity and toxicity, especially relative to the typically zwitterionic properties of normal cell membranes [166]. Amphiphilicity levels and hydrophobic arc size allow the penetration of these peptides through cancerous cell membranes, leading to destabilization of membrane integrity [167,168]. Since they are composed of metabolically and allergenically tolerable amino acids, the risk of undesirable destructive side-reactions is reduced, and they are usually safe and non-toxic compounds. Furthermore, anticancer peptides are also used as vehicles in drug formulations for the improvement of biological properties, targeted drug delivery, or transport through target cell membranes [169]. Several potential anticancer peptides, such as stimuvax, primovax, melanotan, and cilengitide, are in clinical trials [170]. Combination therapy has emerged as an important strategy for fighting cancer in recent years because a single method may not be enough to completely cure the disease and prevent recurrence [159]. For the purpose of synergistic effects, combinations of anti-angiogenic compounds and traditional therapies are currently being investigated in clinical trials and will make anticancer peptide discovery more interesting in the next few years.