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Review

Reptiles as Promising Sources of Medicinal Natural Products for Cancer Therapeutic Drugs

by
Soon Yong Park
1,
Hyeongrok Choi
2 and
Jin Woong Chung
2,*
1
Research Center, Dongnam Institute of Radiological & Medical Sciences, Busan 460333, Korea
2
Department of Biological Science, College of Natural Sciences, Dong-A University, Busan 49315, Korea
*
Author to whom correspondence should be addressed.
Pharmaceutics 2022, 14(4), 874; https://doi.org/10.3390/pharmaceutics14040874
Submission received: 10 March 2022 / Revised: 12 April 2022 / Accepted: 13 April 2022 / Published: 16 April 2022
(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)
Browse Figure
Versions Notes

Abstract

Natural products have historically played an important role as a source of therapeutic drugs for various diseases, and the development of medicinal natural products is still a field with high potential. Although diverse drugs have been developed for incurable diseases for several decades, discovering safe and efficient anticancer drugs remains a formidable challenge. Reptiles, as one source of Asian traditional medicines, are known to possess anticancer properties and have been used for a long time without a clarified scientific background. Recently, it has been reported that extracts, crude peptides, sera, and venom isolated from reptiles could effectively inhibit the survival and proliferation of various cancer cells. In this article, we summarize recent studies applying ingredients derived from reptiles in cancer therapy and discuss the difficulties and prospective development of natural product research.

1. Introduction

Cancer, an intricate genetic disease triggered by mutations that create expression, functional, and/or structural abnormalities in major genes, remains an unconquered disease worldwide [1]. Cancer can promote recurrence and metastasis via uncontrolled growth, high motility, and various survival defense mechanisms induced through complex genetic modifications [2,3,4]. Over the last several decades, highly efficacious cancer therapeutic methods have been developed. Currently, synthetic chemical compounds are commonly used for effective cancer treatment, but they are accompanied by serious side effects, including vomiting, loss of hair and body weight, and functional impairment of organs. Molecular targeted therapy is a novel approach in which molecules specifically bind to membrane proteins, such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), anaplastic lymphoma kinase (ALK), and human epidermal growth factor receptor-2/-3 (HER-2/-3). Alternatively, the molecules inhibit specific signal transducers, including proto-oncogene tyrosine kinase (SRC), proto-oncogene serine/threonine kinase (RAF), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase 1/2 (MEK1/2), mitogen-activated protein kinase (MAPK), the cyclin D1/cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) [5,6,7,8]. Although molecular targeted therapies have fewer side effects than chemical compounds alone, it is difficult to establish a standard therapeutic method because their efficacy is different depending on the tumor type [9,10,11]. Additionally, it might be difficult to find a proper therapeutic target which is at a significantly high level or only expressed in a specific tumor. Cancer immunotherapy is a recently developed technology that suppresses the immune-evasion mechanism of cancer cells and improves the activity of immune cells [12,13,14,15]. For example, immunotherapy can suppress tumor growth by activating T cells via the inhibition of programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1). This binding of cancer cells and T cells is an important immune checkpoint mechanism [16,17,18]. Additionally, chimeric antigen receptor T (CAR-T)-cell therapy is an innovative personalized cancer treatment. T cells that have been isolated from the blood of patients or donors are genetically engineered to enhance their expression of specific receptors and cytotoxicity against cancer cells [19,20,21]. This therapy is a cell-based technology without any cytotoxicity to normal organs. It can be customized according to the type of tumor and the patient’s condition. Despite these advantages, the CAR-T-cell technique is only effective in some blood cancers, such as leukemia, and it has even resulted in the acceleration of tumor progression. Therefore, it is necessary to develop materials or medical technologies that are capable of effectively targeting tumors alone and not normal tissues and organs.
Throughout human history, natural products have been used in various forms from a time when there was no clear scientific verification for their use to the present. Based on the knowledge acquired through experience, natural products have been used for the prevention and treatment of diverse disorders, such as inflammation, hyperpyrexia and infection [22,23,24,25]. With advances in science and technology, it has become possible to select, isolate, and purify key factors possessing medical therapeutic effects. Because natural products are derived from microbes, plants, marine organisms and animals, they have superior physiological stability and safety. Based on these strengths, a number of pharmaceutical companies and research institutes have made various attempts to discover powerful anticancer factors from natural products [26,27]. Many types of active anticancer components derived from plants have already been developed as therapeutic drugs and are currently being used to cure patients. Additionally, marine natural product research, including research on microorganisms, phytoplankton, algae, sponges and fish, has progressed, and the functional roles of bioactive compounds have been clearly verified. Although fewer anticancer molecules have been derived from animals than from plants and marine organisms [28,29,30,31,32], animal-derived components have some benefits, such as efficient biocompatibility, bioactivity, stability and safety to human tissues [33]. Reports have proven the bioactivity of peptides that have been isolated from goat spleens or livers and bovine meat [34,35]. Lactoferrin, which is known to be contained in large amounts in colostrum, has been proven to be a multifunctional glycoprotein that inhibits senescence, inflammation and tumors [36]. Surprisingly, diverse anticancer peptides have been identified from the skin secretions of amphibians. Reptiles have also been used in Asian traditional medicine along with amphibians [37,38,39]. Reptile-derived bioactive components have been isolated through different extraction processes, and their therapeutic effects on cancer have been reported in the past two decades. Anticancer research using reptile-derived components has abundant potential as well as a high value because it is still in the early development stage [40,41].
Here, we discuss the development of cancer therapeutic drugs that are based on bioactive natural products and derived from sources including plants, marine organisms and animals. Specifically, we focus on recent research that has uncovered anticancer components derived from reptiles that may help to overcome challenges in cancer therapy.

2. Natural Sources of Bioactive Cancer Therapeutic Components

2.1. Plants

Since ancient times, terrestrial plants have been a very important source of medicines used for preventing or treating various diseases. Several anticancer drugs currently in use are derived from terrestrial plants (Table 1). Vincristine and vinblastine, typical anticancer drugs containing components derived from plants, are vinca alkaloids derived from the leaves of Catharanthus roseus (also known as Vinca rosea or the Madagascar periwinkle plant). Vincristine and vinblastine are effective against some types of cancer, such as acute leukemia, Hodgkin lymphoma, lymphosarcoma, testicular cancer and lung cancer [42,43]. They inhibit the growth of cancer cells by inhibiting tubulin function during cell division. Paclitaxel was isolated from Taxus brevifolia, the pacific yew. Paclitaxel is an antiproliferative drug that promotes microtubule assembly and stability, and it has been reported to be effective in the treatment of ovarian, cervical, breast, lung and pancreatic cancer [44]. In addition, numerous plant-derived anticancer components, such as resveratrol, curcumin, epigallocatechin gallate, quercetin, rutin and ginsenoside, have been discovered and developed as drugs [45,46,47,48,49,50,51,52,53]. Many types of terrestrial plant-derived anticancer components have also been discovered and developed as effective drugs. Therefore, in the future, research on the development of drugs derived from plant components might have great potential to improve efficiency in applied studies.

2.2. Marine Organisms

Marine compounds possess unlimited potential for drug discovery because there are likely to be many unknown organisms and untapped areas of research. Marine research for drug development has been underway since the 1980s. Various anticancer peptides have been isolated from diverse marine organisms such as algae, sponges and fish (Table 2). Lurbinectedin is an alkaloid isolated from Ecteinascidia turbinata that might promote cancer cell death by inhibiting gene transcription [29]. Tisotumab vedotin, known by the brand name Tivdak, is an antibody–drug conjugate (ADC) used to treat cervical cancer. Tisotumab vedotin that has been isolated from Dolabella auricularia might induce apoptosis through cell cycle arrest by binding to the tissue factor (CD142) on the cancer cell surface and releasing monomethyl auristatin E (MMAE) in the cell [29]. Additionally, many types of alkaloids, peptides and ADC anticancer drugs are being continuously developed. According to recent reports, many marine natural products isolated from fish, seaweed, fungi, mangroves, microalgae, cone snails, sea hares and mollusks can inhibit cancer progression both in vivo and in vitro through cell lysis, necrosis and apoptosis [54,55,56,57,58,59]. Marine bioactive components might attenuate several types of cancer cells, such as breast, lung, bladder, prostate, melanoma and leukemia cells [60,61,62]. It is expected that marine natural products will continue to have high potential because there are still numerous unexplored marine organisms.

3. Cancer Therapeutic Research Using Reptile-Derived Components

Drugs derived from reptiles have long been widely used as a source of nourishment, nutritional tonics and disease treatment in Asia. In general, powders and other derivatives can be made from dried reptiles after the removal of the intestines, or extracts can be created by soaking the whole reptile in alcohol. Recently, the inflammatory and tumor-suppressive effects of components derived from reptiles have been experimentally proven, and anticancer research is being conducted with various formulations generated with different extraction methods. Typically, cancer therapeutic studies are performed using extracts, crude peptides, sera and/or venom isolated from reptiles through several extraction methods (Table 3).

3.1. Extracts

Reptile-derived extracts, which are very similar to traditionally derived agents, have been proven to have excellent tumor-suppressive effects. According to the reported studies, aqueous extracts of Gekko swinhonis inhibited the proliferation and differentiation of human hepatic cancer cell lines such as L-02 and Bel-7402 [72]. Additionally, aqueous extracts of Gekko subpalmatus Gunther exhibited antitumor effects in vivo and inhibited the growth of the Bel-7402 cell line [73]. Moreover, they decreased the expression of alpha fetoprotein (AFP), which is a malignant phenotype marker of liver tumors. Extracts of Gekko japonicus showed antitumor effects against the human esophageal carcinoma EC9703 and mouse sarcoma S180 cell lines in experiments in vitro and in vivo [74]. Surprisingly, extracts derived from Cyrtopodion scabrum using ethanol and distilled water showed selective anticancer effects against the human breast cancer cell line MCF7 and human colon cancer cell line SW-742 through the inhibition of growth and migration, and they had no effect on normal mesenchymal stem cells [75]. In addition, the aqueous protein extracts of Eublepharis macularius induced apoptosis only in human cancer cell lines, such as bladder cancer 5637 and cervical cancer HeLa cells, via the inhibition of the PI3K/Akt signaling pathway, and without any effect on normal cells, including C2C12, NIH3T3, MEF, HEK293, Hs27 and NuFF cells [76,77]. Jeong et al. and Kim et al., proved the anticancer effects of proteins or peptides through several experiments using heat-inactivated extracts. Furthermore, these extracts suppressed the proliferation and survival of cancer cells through G2/M cell cycle arrest and the caspase-dependent apoptosis pathway via the inhibition of PI3K/Akt signaling in the human non-small-cell lung cancer cell line A549 and the mouse lung cancer cell line Lewis lung carcinoma (LLC). In particular, the intravenous injection of these protein extracts showed pharmaceutical potential by reducing tumor volume via the suppression of Akt phosphorylation in vivo. According to this paper, Lee et al. performed the fractionation and isolation of reptile extracts, and several candidates were identified as major anticancer components. Additionally, they identified the various proteins contained in the extracts by performing proteomics analyses. This revealed the interaction network, the biological process that categorizes differentially expressed proteins and the involved cellular-signaling pathways of all identified proteins contained in the extracts [78]. Finally, these studies explicitly demonstrated that the aqueous protein extracts of Eublepharis macularius might possess therapeutic effects against many types of human cancer cells via in vitro and in vivo experiments.
Crocodile choline, a bioactive component derived from Crocodylus siamensis, promoted cell death in gastric cancer cell lines, including the BGC823, MGC803, SGC7901 and MKN28 cell lines, without side effects on the normal gastric cell line GESI [79]. This agent also induced apoptosis through G2/M cell cycle arrest in the BGC823 cell line. In experiments conducted in vivo, the intragastric (i.g.) administration of crocodile choline not only suppressed tumor growth but also had no striking effects on other internal organs. Additionally, the lysates of several organs of Crocodylus palustris, such as the heart, lungs, intestine and brain, showed a high cytotoxicity against the human prostate cancer cell line PC3 [80]. In addition, the aqueous extracts of white blood cells derived from Crocodylus siamensis induced apoptosis in the human cervical cancer cell line HeLa through the mitochondria/caspase-3/caspase-9-mediated intrinsic pathway and effectively inhibited the proliferation, migration and invasion of cancer cells [81,82]. Furthermore, the extracts promoted apoptosis in the human cancer cell lines LU1, LNCaP, PC3, MCF and CaCo2 through G2/M phase cell cycle arrest [83]. These studies suggest that various extracts derived from crocodile might be useful materials in the development of pharmaceuticals.
Aqueous extracts of turtle shell derived from Chinemys reevesii, Cuora aurocapitata or Trachemys scripta promoted cell death in the human leukemia cell line HL60 and the human liver cancer cell line HepG2 [84]. Although research is still in the early stages, these studies suggest that extracts of reptiles could be effective drug candidates for cancer therapy.

3.2. Crude Peptides

Peptide mixtures or crude peptides isolated from reptiles may play an important role in drug development and might provide promising options for cancer therapy. Protein and functional peptides are safe drugs that have an excellent cell permeability and minimal potential to elicit an immune-rejection response. Therefore, peptides derived from reptiles could be key drug candidates. A sulfated polysaccharide–protein complex can be extracted from the dried whole body of Gekko swinhonis Guenther using polar solvents. Several features of the protein complex were analyzed through high-performance liquid chromatography, gas chromatography–mass spectrometry, gas chromatography and NMR spectroscopy. Remarkably, the complex inhibited the proliferation and migration abilities of the human hepatocellular carcinoma cell line SMMC-7721 [85]. Additionally, the crude peptides isolated from alcohol extracts of dried whole Gekko japonicus suppressed the proliferation of the human liver carcinoma cell line HepG2 and promoted apoptosis through Bcl-2/Bax pathway regulation [86]. These crude peptides significantly reduced the tumor weight as well as the expression of VEGF in xenograft tumors derived from the mouse liver carcinoma cell line H22. Similarly, a polypeptide mixture extracted from Gekko japonicus powder effectively inhibited the proliferation and induced the apoptosis of the human liver carcinoma cell line HepG2 [87]. Interestingly, differentially expressed genes in HepG2 cells treated with the polypeptide mixture were analyzed through RNA-Seq, gene ontology and protein–protein interaction analyses. Additional experiments demonstrated that several genes involved in the apoptosis induced by the peptide mixture promote reactive oxygen species (ROS)-related processes and the unfolded protein response (UPR). These studies show that if the identity of reptile-derived peptides is determined, valuable drugs based on these targets and related signaling pathways could be developed.

3.3. Sera and Bile

Anticancer studies based on body fluids rather than whole-body-derived components of reptiles are rare because a relatively fresher sample is needed. Nevertheless, studies have verified the anticancer properties of reptile serum and bile. Serum isolated from Varanus salvator blood showed cytotoxicity against HeLa cells without affecting the normal human keratinocyte cell line HaCaT [88]. The sera of Malayopython reticulatus and Cuora amboinensis kamaroma also exerted anticancer effects against the human cancer cell lines HeLa, PC3 and MCF7 [88]. This study identified several compounds, including purine, alpha-naphthylthiourea (ANTU), 6E, 9E-octadecadienoic acid, allo-inositol and uric acid, that possess various bioactivities from the sera of these reptiles using LC–MS/MS analysis.
Animal bile has been used as a natural drug to strengthen stamina and immunity for thousands of years. Bile contains many bile acids, such as cholic acid and deoxycholic acid, that play a role in physiological functions. Bile juice squeezed from the gallbladders of Crocodylus siamensis promoted apoptosis in the human non-small-cell lung cancer cell line NCI-H1299 through the mitochondria/caspase-3/caspase-9-mediated intrinsic pathway, and effectively suppressed tumorigenesis and growth in athymic nude mice [89]. These findings could expand the pool of natural drug development for cancer therapy in the near future.

3.4. Venom

Effective therapeutic factors that have been diluted or purified from venom have been used to treat diseases. Bee venom, for example, is composed of approximately 40 factors, and among these, melittin and apamin may enhance the immune system through the promotion of hormone metabolism, blood circulation and immune cell activation. This occurs by stimulating the anterior pituitary or adrenal cortex [109,110]. Botulinum toxin derived from Clostridium botulinum is a neurotoxic protein that blocks the release of acetylcholine from the axon terminal of neurons. Botulinum toxin types A and B are applied in the medical field to treat the hyperactive responses of muscles and neurons [111,112,113]. Research on reptile-derived venom has also been conducted, and several effects on cancer cells have been demonstrated. Lectin purified from Macrovipera lebetina, BnSP-6 and Lys-49 phospholipase A2 (PLA2) purified from Bothrops pauloensis, NN-3 purified from Naja naja oxiana, and chlorotoxin purified from Leiurus quinquestriatus were analyzed to determine their structure, amino acid sequence and anticancer effect against MDA-MB-231 cells [90,91,92,93]. Additionally, macrovipecetin, a C-type lectin from Macrovipera lebetina, suppressed the migration, invasion and proliferation of the human melanoma cell line SK-MEL-28 [94]. Crotoxin, a toxin derived from Crotalus durissus terrificus and cytotoxin 2 derived from Naja naja oxiana decreased the viability of MCF7aro cells via the inhibition of the extracellular signal-regulated kinase (ERK) pathway, inhibited cell migration by inducing the apoptosis of MCF7 cells, and showed an anticancer effect on lung cancer cells in A549 cells through the activation of the caspase-3 and p38 pathways [95,96,97]. Daboialectin, a C-type lectin derived from Daboia russelii, effectively inhibited cell motility by promoting the cytoskeletal damage and apoptosis of A549 cells [98]. Additionally, cytotoxin 1 (a polypeptide consisting of 60 amino acids from Naja atra) caused the necroptosis of the leukemia cell lines HL-60 and KG1a [99]. Disintegrin isolated from Echis multisquamatus exerted antiproliferative action against HeLa cells [100]. The venom extracts of Vipera latifii or Naja hage showed anticancer effects against the hepatocellular carcinoma cell lines HepG2 and Huh7.5 [101,102]. Additionally, the venom extracts of Walterinnesia aegyptia induced apoptosis through the activation of the caspase-3 pathway in human breast cancer cell lines MDA-MB-231 and MCF7 [103]. The novel recombinant protein cytotoxin 2 derived from Naja naja oxiana inhibited the transforming growth factor/suppressor of mothers against the decapentaplegic (TGFβ/SMAD) signaling pathway, and the expression of matrix metalloproteinase 3 (MMP3) in the human melanoma cell line SK-MEL-03, without side effects on the normal fibroblast cell line HFF-2 [104]. Jararhagin toxin from Bothrops jararaca reduced proliferative ability through the activation of the caspase-3 pathway in the murine melanoma cell line B16F10 [105]. L-Amino acid oxidase isolated from Cerastes vipera showed powerful cytotoxicity against MCF7, HepG2, A549, and PC3 cells and the human colon cancer cell line HCT116, compared with doxorubicin [106,107]. The activated crude venom of Cerastes cerastes by irradiation (Co-60 gamma rays) induced apoptosis via G2/M phase cell cycle arrest in the human non-small-cell lung cancer cell line A549 and the human prostate cancer cell line PC3 [108]. These studies demonstrated that isolation, purification and functional peptide analysis can be used to develop diverse venom-derived products as effective cancer therapeutic drugs.

4. Conclusions and Perspectives Regarding Reptile-Derived Products as Natural Pharmaceutical Materials

Therapeutic bioactive components derived from various reptiles are valuable natural sources with the potential to overcome the shortcomings of current cancer therapies (Figure 1). In the past, reptile components have been used in the form of extracts, powders, pills and liquors. Additionally, toxic ingredients in venom have been diluted or weakened for use. In Asian medicine, reptile-derived components are known to have pharmaceutical effects against several disorders, such as inflammation, nephrolithiasis, eczema and tumors. In recent years, advanced analysis techniques have made it possible to isolate components derived from reptiles and identify their pharmacological effects, structures, functions, and mechanisms. Interestingly, studies have structurally minimized fragments of crotamine and crotalicidin isolated from Crotalus durissus terrificus venom for application in medicinal technology [114]. However, the development of reptile-derived anticancer components is still in the early research stage, and several problems need to be solved in order for it to be used as a more stable and efficient therapeutic agent. The constant collection, maintenance, and sampling of reptile-derived anticancer components are important in the development of natural medicinal products. Library screening establishment, a systematic process for active substance identification, including sample purification and structural analysis, is essential for novel drug research. Additionally, the combination of reptile-derived anticancer components with various drug delivery system technologies such as medical implantable devices, small functional peptides, nanoparticles, liposomes, immunoliposomes, and antibody-drug conjugates (ADCs), might enable more safe and efficient pharmaceutical therapies [115,116,117,118,119,120,121]. If reptile-derived anticancer components and advanced technologies are actively fused and developed, an innovative cancer therapeutic drug platform could be organized based on a definite mechanism of action according to the individual components. In conclusion, reptile-derived components with therapeutic potential, such as extracts, peptides, sera, bile and venom, which are still in the early stages of research, will be an excellent novel source of medicines for cancer therapy in the future.

Author Contributions

Conceptualization, S.Y.P. and J.W.C.; investigation, S.Y.P., H.C., and J.W.C.; writing—original draft preparation, S.Y.P. and J.W.C. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Research Foundation of Korea (NRF-2020R1F1A1070475).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Curtius, K.; Wright, N.A.; Graham, T.A. An evolutionary perspective on field cancerization. Nat. Rev. Cancer 2018, 18, 19–32. [Google Scholar] [CrossRef] [PubMed]
  2. Nia, H.T.; Munn, L.L.; Jain, R.K. Physical traits of cancer. Science 2020, 370, eaaz0868. [Google Scholar] [CrossRef] [PubMed]
  3. Mierke, C.T. The matrix environmental and cell mechanical properties regulate cell migration and contribute to the invasive phenotype of cancer cells. Rep. Prog. Phys. 2019, 82, 064602. [Google Scholar] [CrossRef] [PubMed]
  4. Zanotelli, M.R.; Reinhart-King, C.A. Mechanical forces in tumor angiogenesis. Adv. Exp. Med. Biol. 2018, 1092, 91–112. [Google Scholar] [PubMed]
  5. Lee, Y.T.; Tan, Y.J.; Oon, C.E. Molecular targeted therapy: Treating cancer with specificity. Eur. J. Pharmacol. 2018, 834, 188–196. [Google Scholar] [CrossRef] [PubMed]
  6. Lev, S. Targeted therapy and drug resistance in triple-negative breast cancer: The EGFR axis. Biochem. Soc. Trans. 2020, 48, 657–665. [Google Scholar] [CrossRef] [PubMed]
  7. Ulfo, L.; Costantini, P.E.; Giosia, M.; Danielli, A.; Calvaresi, M. EGFR-targeted photodynamic therapy. Pharmaceutics 2022, 14, 241. [Google Scholar] [CrossRef]
  8. Tang, Y.; Chen, Y.; Zhang, Z.; Tang, B.; Zhou, Z.; Chen, H. Nanoparticle-based RNAi therapeutics targeting cancer stem cells: Update and prospective. Pharmaceutics 2021, 13, 2116. [Google Scholar] [CrossRef]
  9. Zafar, A.; Wang, W.; Liu, G.; Wang, X.; Xian, W.; Mckeon, F.; Foster, J.; Zhou, J.; Zhang, R. Molecular targeting therapies for neuroblastoma: Progress and challenges. Med. Res. Rev. 2021, 41, 961–1021. [Google Scholar] [CrossRef]
  10. Kijanka, M.; Dorresteijn, B.; Oliveira, S.; van Bergen en Henegouwen, P.M. Nanobody-based cancer therapy of solid tumors. Nanomedicine 2015, 10, 161–174. [Google Scholar] [CrossRef]
  11. Curigliano, G.; Criscitiello, C. Successes and limitations of targeted cancer therapy in breast cancer. Prog. Tumor. Res. 2014, 41, 15–35. [Google Scholar] [PubMed]
  12. Gu, Z.; Da Silva, C.G.; Van der Maaden, K.; Ossendorp, F.; Cruz, L.J. Liposome-based drug delivery systems in cancer immunotherapy. Pharmaceutics 2020, 12, 1054. [Google Scholar] [CrossRef] [PubMed]
  13. Kennedy, L.B.; Salama, A.K.S. A review of cancer immunotherapy toxicity. CA Cancer J. Clin. 2020, 70, 86–104. [Google Scholar] [CrossRef] [PubMed]
  14. O’Donnell, J.S.; Teng, M.W.L.; Smyth, M.J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol. 2019, 16, 141–167. [Google Scholar] [CrossRef] [PubMed]
  15. Trapani, J.A.; Darcy, P.K. Immunotherapy of cancer. Aust. Fam. Physician. 2017, 46, 194–199. [Google Scholar] [PubMed]
  16. Gong, J.; Chehrazi-Raffle, A.; Reddi, S.; Salgia, R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: A comprehensive review of registration trials and future considerations. J. Immunother. Cancer. 2018, 6, 8. [Google Scholar] [CrossRef] [PubMed]
  17. Ai, L.; Xu, A.; Xu, J. Roles of PD-1/PD-L1 pathway: Signaling, cancer, and beyond. Adv. Exp. Med. Biol. 2020, 1248, 33–59. [Google Scholar]
  18. Chamoto, K.; Hatae, R.; Honjo, T. Current issues and perspectives in PD-1 blockade cancer immunotherapy. Int. J. Clin. Oncol. 2020, 25, 790–800. [Google Scholar] [CrossRef]
  19. Nair, R.; Westin, J. CAR T-cells. Adv. Exp. Med. Biol. 2020, 1244, 215–233. [Google Scholar]
  20. Mas, S.; Li, X.; Wang, X.; Cheng, L.; Li, Z.; Zhang, C.; Ye, Z.; Qian, Q. Current progress in CAR-T cell therapy for solid tumors. Int. J. Biol. Sci. 2019, 15, 2548–2560. [Google Scholar]
  21. Hong, M.; Clubb, J.D.; Chen, Y.Y. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell 2020, 38, 473–488. [Google Scholar] [CrossRef] [PubMed]
  22. Katz, L.; Bltz, R.H. Natural product discovery: Past, present, and future. J. Ind. Microbiol. Biotechnol. 2016, 43, 155–176. [Google Scholar] [CrossRef] [PubMed]
  23. Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod. 2020, 83, 770–803. [Google Scholar] [CrossRef] [PubMed]
  24. Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629–661. [Google Scholar] [CrossRef]
  25. Yang, C.; Zhang, W.; Dong, X.; Fu, C.; Yuan, J.; Xu, M.; Liang, Z.; Qiu, C.; Xu, C. A natural product solution to aging and aging-associated diseases. Pharmacol. Ther. 2020, 216, 107673. [Google Scholar] [CrossRef]
  26. Atanasov, A.G.; Waltenberger, B.; Pferschy-Wenzig, E.M.; Linder, T.; Wawrosch, C.; Uhrin, P.; Temml, V.; Wang, L.; Schwaiger, S.; Heiss, E.H.; et al. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol. Adv. 2015, 33, 1582–1614. [Google Scholar] [CrossRef]
  27. Choudhary, S.; Singh, P.K.; Verma, H.; Singh, H.; Silakari, O. Success stories of natural product-based hybrid molecules for multi-factorial diseases. Eur. J. Med. Chem. 2018, 151, 62–97. [Google Scholar] [CrossRef]
  28. Blunt, J.W.; Copp, B.R.; Keyzers, R.A.; Munro, M.H.G.; Prinsep, M.R. Marine natural products. Nat. Prod. Rep. 2017, 34, 235–294. [Google Scholar] [CrossRef]
  29. Papon, N.; Copp, B.R.; Courdavault, V. Marine drugs: Biology, pipelines, current and future prospects for production. Biotechnol. Adv. 2022, 54, 107871. [Google Scholar] [CrossRef]
  30. Liang, X.; Luo, D.; Luesch, H. Advances in exploring the therapeutic potential of marine natural products. Pharmacol. Res. 2019, 147, 104373. [Google Scholar] [CrossRef]
  31. Yun, C.W.; Kim, H.J.; Lee, S.H. Therapeutic application of diverse marine-derived natural products in cancer therapy. Anticancer Res. 2019, 39, 5261–5284. [Google Scholar] [CrossRef] [PubMed]
  32. Khalif, S.A.M.; Elias, N.; Farag, M.A.; Chen, L.; Saeed, A.; Hegazy, M.F.; Moustafa, M.S.; Abd Ei-Wahed, A.; Ai-Mousawi, S.M.; Musharraf, S.G.; et al. Marine natural products: A source of novel anticancer drugs. Mar. Drugs 2019, 17, 491. [Google Scholar] [CrossRef] [PubMed]
  33. Napavichayanun, S.; Aramwit, P. Effect of animal products and extracts on wound healing promotion in topical apllications: A review. J. Biomater. Sci. Plym. Ed. 2017, 28, 703–729. [Google Scholar] [CrossRef] [PubMed]
  34. Su, X.; Donga, C.; Zhang, J.; Su, L.; Wang, X.; Cui, H.; Chen, Z. Combination therapy of anti-cancer bioactive peptide with Cisplatin decreases chemotherapy dosing and toxicity to improve the quality of life in xenograft nude mice bearing human gastric cancer. Cell. Biosci. 2014, 4, 7. [Google Scholar] [CrossRef] [PubMed]
  35. Jang, A.; Jo, C.; Kang, K.; Lee, M. Antimicrobial and human cancer cell cytotoxic effect of synthetic angiotensin-converting enzyme (ACE) inhibitory peptides. Food Chem. 2008, 107, 327–336. [Google Scholar] [CrossRef]
  36. Wang, L.; Dong, C.; Li, X.; Han, W.; Su, X. Anticancer potential of bioactive peptides from animal sources (Review). Oncol. Rep. 2017, 38, 637–651. [Google Scholar] [CrossRef]
  37. Amiche, M. Amphibian skin as a source of therapeutic peptides. Biol. Aujourdhui 2016, 210, 101–117. [Google Scholar] [CrossRef]
  38. Conclon, J.M.; Mechkarska, M.; Lukic, M.L.; Flatt, P.R. Potential therapeutic applications of multifunctional host-defense peptides from frog skin as anti-cancer, anti-viral, immunomodulatory, and anti-diabetic agents. Peptides 2014, 57, 67–77. [Google Scholar] [CrossRef]
  39. Lu, C.X.; Nan, K.J.; Lei, Y. Agents from amphibians with anticancer properties. Anticancer Drugs 2008, 19, 931–939. [Google Scholar] [CrossRef]
  40. Li, L.; Huang, J.; Lin, Y. Snake venoms in cancer therapy: Past, present and future. Toxins 2018, 10, 346. [Google Scholar] [CrossRef]
  41. Calderon, L.A.; Sobrinho, J.C.; Zaqueo, K.D.; Moura, A.A.; Grabner, A.N.; Mazzi, M.V.; Marcussi, S.; Nomizo, A.; Fernandes, C.F.C.; Zuliani, J.P.; et al. Antitumoral activity of snake venom proteins: New trends in cancer therapy. Biomed. Res. Int. 2014, 2014, 203639. [Google Scholar] [CrossRef] [PubMed]
  42. Skubnik, J.; Pavlickova, V.S.; Ruml, T.; Rimpelova, S. Vincristine in combination therapy of cancer: Emerging trends in clinics. Biology 2021, 10, 849. [Google Scholar] [CrossRef] [PubMed]
  43. Salerni, B.L.; Bates, D.J.; Albershardt, T.C.; Lowrey, C.H.; Eastman, A. Vinblastine induces acute, cell cycle phase-independent apoptosis in some leukemias and lymphomas and can induce acute apoptosis in others when Mcl-1 is suppressed. Mol. Cancer Ther. 2010, 9, 791–802. [Google Scholar] [CrossRef]
  44. Yang, Y.H.; Mao, J.W.; Tan, X.L. Research progress on the souce, production, and anti-cancer mechanisms of paclitaxel. Chin. J. Nat. Med. 2020, 18, 890–897. [Google Scholar] [PubMed]
  45. Yang, Y.; Paik, J.H.; Cho, D.; Cho, J.A.; Kim, C.W. Resveratrol induces the suppression of tumor-derived CD4+CD25+ regulatory T cells. Int. Immunopharmacol. 2008, 8, 542–547. [Google Scholar] [CrossRef] [PubMed]
  46. Giordano, A.; Tommonaro, G. Curcumin and Cancer. Nutrients 2019, 11, 2376. [Google Scholar] [CrossRef] [PubMed]
  47. Jin, T.; Wu, H.; Wang, Y.; Peng, H. Capsaicin induces immunogenic cell death in human osteosarcoma cells. Exp. Ther. Med. 2016, 12, 765–770. [Google Scholar] [CrossRef]
  48. Lecumberri, E.; Dupertuis, Y.M.; Miralbell, R.; Pichard, C. Green tea polyphenol epigallocatechin-3-gallate (EGCG) as adjuvant in cancer therapy. Clin. Nutr. 2013, 32, 893–903. [Google Scholar] [CrossRef]
  49. Sztiller-Sikorska, M.; Czyz, M. Parthenolide as cooperating agent for anti-cancer treatment of various malignancies. Pharmaceuticals 2020, 13, 194. [Google Scholar] [CrossRef]
  50. Li, X.; Huang, R.; Li, M.; Zhu, Z.; Chen, Z.; Cui, L.; Luo, H.; Luo, L. Parthenolide inhibits the growth on non-small cell lung cancer by targeting epidermal growth factor receptor. Cancer Cell Int. 2020, 20, 561. [Google Scholar] [CrossRef]
  51. Sun, M.; Ye, Y.; Xiao, L.; Duan, X.; Zhang, Y.; Zhang, H. Anticancer effects of ginsenoside Rg3 (Review). Int. J. Mol. Med. 2017, 39, 507–518. [Google Scholar] [CrossRef] [PubMed]
  52. You, W.; Di, A.; Zhang, L.; Zhao, G. Effects of wogonin on the growth and metastasis of colon cancer through the Hippo signaling pathway. Bioengineered 2022, 13, 2586–2597. [Google Scholar] [CrossRef] [PubMed]
  53. Ruibin, J.; Danying, W.; Chihong, Z.; Jianguo, F.; Linhui, G. Therapy effects of wogonin on ovarian cancer cells. Biomed. Res. Int. 2017, 2017, 9381513. [Google Scholar] [CrossRef] [PubMed]
  54. Lin, Y.; Qi, X.; Liu, H.; Xue, K.; Xu, S.; Tian, Z. The anti-cancer effects of fucoidan: A review of both in vivo and in vitro investigations. Cancer Cell Int. 2020, 20, 154. [Google Scholar] [CrossRef] [PubMed]
  55. Watanabe, J.; Minami, M.; Kobayashi, M. Antitumor activity of TZT-1027 (Soblidotin). Anticancer Res. 2006, 36, 1973–1981. [Google Scholar]
  56. Natsume, T.; Watanabe, J.; Koh, Y.; Fuijo, N.; Ohe, Y.; Horiuchi, T.; Saijo, N.; Nishio, K.; Kobayashi, M. Antitumor activity of TZT-1027 (Soblidotin) against vascular endothelial growth factor-secreting human lung cancer in vivo. Cancer Sci. 2003, 94, 826–833. [Google Scholar] [CrossRef]
  57. Atallah, J.; Khachfe, H.H.; Berro, J.; Assi, H.I. The use of heparin and heparin-like molecules in cancer treatment: A review. Cancer Treat. Res. Commun. 2020, 24, 100192. [Google Scholar] [CrossRef]
  58. Niers, T.M.H.; Klerk, C.P.W.; DiNisio, M.; Noorden, C.J.F.V.; Buller, H.R.; Reitsma, P.H.; Richel, D.J. Mechanisms of heparin induced anti-cancer activity in experimental cancer models. Crit. Rev. Oncol. Hematol. 2007, 61, 195–207. [Google Scholar] [CrossRef]
  59. Magalhaes, K.D.; Costa, L.S.; Fidelis, G.P.; Oliveira, R.M.; Nobre, L.T.D.B.; Dantas-Santos, N.; Camara, R.B.G.; Albuquerque, I.R.L.; Cordeiro, S.L.; Sabry, D.A.; et al. Anticoagulant, antioxidant and antitumor activities of heterofucans from the seaweed Dictyopteris delicatula. Int. J. Mol. Sci. 2011, 12, 3352–3365. [Google Scholar] [CrossRef]
  60. Heiferman, M.J.; Salabat, M.R.; Ujiki, M.B.; Strouch, M.J.; Cheon, E.C.; Silverman, R.B.; Bentrem, D.J. Sansalvamide induces pancreatic cancer growth arrest through changes in the cell cycle. Anticancer Res. 2010, 30, 73–78. [Google Scholar]
  61. Vasko, R.C.; Rodriguez, R.A.; Cunningham, C.N.; Ardi, V.C.; Agard, D.A.; McAlpine, S.R. Mechanistic studies of Sansalvamide A-amide: An allosteric modulator of Hsp90. ACS Med. Chem. Lett. 2010, 1, 4–8. [Google Scholar] [CrossRef] [PubMed]
  62. Galmarini, C.M.; D’Incalci, M.; Allavena, P. Trabectedin and plitidepsin: Drugs from the sea that strike the tumor microenvironment. Mar. Drugs. 2014, 12, 719–733. [Google Scholar] [CrossRef] [PubMed]
  63. Turner, T.; Jackson, W.H.; Pettit, G.R.; Wells, A.; Kraft, A.S. Treatment of human prostate cancer cells with dolastatin 10, a peptide isolated from a marine shell-less mollusk. Prostate 1998, 34, 175–181. [Google Scholar] [CrossRef]
  64. Gao, G.; Wang, Y.; Hua, H.; Li, D.; Tang, C. Marine antitumor peptide dolastatin 10: Biological activity, structural modification and synthetic chemistry. Mar. Drugs 2021, 19, 363. [Google Scholar] [CrossRef]
  65. Swami, U.; Shah, U.; Goel, S. Eribulin in cancer treatment. Mar. Drugs 2015, 13, 5016–5058. [Google Scholar] [CrossRef]
  66. Fenical, W.; Jensen, P.R.; Palladino, M.A.; Lam, K.S.; Lloyd, G.K.; Potts, B.C. Discovery and development of the anticancer agent salinosporamide A (NPI-0052). Bioorg. Med. Chem. 2009, 17, 2175–2180. [Google Scholar] [CrossRef]
  67. Gulder, T.A.M.; Moore, B.S. Salinosporamide natural products: Potent 20 S proteasome inhibitors as promising cancer chemotherapeutics. Angew. Chem. Int. Ed. Engl. 2010, 49, 9346–9367. [Google Scholar] [CrossRef]
  68. Wu, L.; Ye, K.; Jiang, S.; Zhou, G. Marine power on cancer: Drugs, lead compounds, and mechanisms. Mar. Drugs 2021, 19, 488. [Google Scholar] [CrossRef]
  69. Raninga, P.V.; Lee, A.; Sinha, D.; Dong, L.F.; Datta, K.K.; Lu, X.; Croft, P.K.; Dutt, M.; Hill, M.; Pouliot, N.; et al. Marizomib suppresses triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition. Theranostics 2020, 1, 5259–5275. [Google Scholar] [CrossRef]
  70. Chhikara, B.S.; Parang, K. Dvelopment of cytarabine prodrugs and delivery systems for leukemia treatment. Expert Opin. Drug Deliv. 2010, 7, 1399–1414. [Google Scholar] [CrossRef]
  71. Ocio, E.M.; Maiso, P.; Chen, X.; Garayoa, M.; Alvarez-Fernandez, G.; San-Segundo, L.; Vilanova, D.; Lopez-Corral, L.; Montero, J.C.; Hernandez-Iglesias, T.; et al. Zalypsis: A novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks. Blood 2009, 113, 3781–3791. [Google Scholar] [CrossRef] [PubMed]
  72. Wu, X.; Chen, D.; Xie, G.R. Effects of Gekko sulfated polysaccharide on the proliferation and differentiation of hepatic cancer cell line. Cell Biol. Int. 2006, 30, 659–664. [Google Scholar] [CrossRef] [PubMed]
  73. Wang, Y.X.; Gu, X.X.; Geng, D.; Sun, H.Y.; Wang, C.M.; Jiang, G.X.; Hou, X.N.; Ma, C.H. Differentiation of bel-7402 human hepatocarcinoma cells induced by aqueous extracts of fresh gecko (AG) and its anti-tumor activity in vivo. J. Ethnopharmacol. 2014, 155, 1583–1588. [Google Scholar] [CrossRef] [PubMed]
  74. Liu, F.; Wang, J.G.; Wang, S.Y.; Li, Y.; Wu, Y.P.; Xi, S.M. Antitumor effect and mechanism of Gecko on human esophageal carcinoma cell lines in vitro and xenografted sarcoma 180 in Kunming mice. World J. Gastroenterol. 2008, 14, 3990–3996. [Google Scholar] [CrossRef] [PubMed]
  75. Amiri, A.; Namavari, M.; Rashidi, M.; Fahmidehkar, M.A.; Seghatoleslam, A. Inhibitory effects of Cyrtopodion scabrum extract on growth of human breast and colorectal cancer cells. Asian Pac. J. Cancer Prev. 2015, 16, 5465–5570. [Google Scholar] [CrossRef] [PubMed][Green Version]
  76. Kim, G.Y.; Park, S.Y.; Jo, A.; Kim, M.; Leem, S.H.; Jun, W.J.; Shim, S.I.; Lee, S.C.; Chung, J.W. Gecko proteins induce the apoptosis of bladder cancer 5637 cells by inhibiting Akt and activating the intrinsic caspase cascade. BMB Rep. 2015, 48, 531–536. [Google Scholar] [CrossRef]
  77. Jeong, A.J.; Chung, C.N.; Kim, H.J.; Bae, K.S.; Choi, S.; Jun, W.J.; Shim, S.I.; Kang, T.H.; Leem, S.H.; Chung, J.W. Gecko proteins exert anti-tumor effect against cervical cancer cells via PI3-kinase/Akt pathway. Korean J. Physiol. Pharmacol. 2012, 16, 361–365. [Google Scholar] [CrossRef]
  78. Lee, J.E.; Lee, D.G.; Park, S.Y.; Jo, A.; Kim, H.K.; Han, J.; Min, J.K.; Chung, J.W. Gekkonidae, lizard tail extracts elicit apoptotic response against non-small lung cancer via inhibiting Akt signaling. Biomed. Pharmacother. 2019, 116, 109050. [Google Scholar]
  79. Mao, X.M.; Fu, Q.R.; Li, H.L.; Zheng, Y.H.; Chen, S.M.; Hy, X.Y.; Chen, Q.X.; Chen, Q.H. Crocodile choline from Crocodylus siamensis induces apoptosis of human gastric cancer. Tumour Biol. 2017, 39, 1010428317694320. [Google Scholar] [CrossRef]
  80. Siddiqui, R.; Jeyamogan, S.; Ali, S.M.; Abbas, F.; Sagatheva, K.A.; Khan, N.A. Crocodiles and alligators: Antiamoebic and antitumor compounds of crocodiles. Exp. Parasitol. 2017, 183, 194–200. [Google Scholar] [CrossRef]
  81. Patathananone, S.; Thammasirirak, S.; Daduang, J.; Chung, J.G.; Temsiripong, Y.; Daduang, S. Bioactive compounds from crocodile (Crocodylus siamensis) white blood cells induced apoptotic cell death in HeLa cells. Environ. Toxicol. 2016, 31, 986–987. [Google Scholar] [CrossRef] [PubMed]
  82. Patathananone, S.; Thammasirirak, S.; Daduang, J.; Chung, J.G.; Temsiripong, Y.; Daduang, S. Inhibition of HeLa cells metastasis by bioactive compounds in crocodile (Crocodylus siamensis) white blood cells extract. Environ. Toxicol. 2016, 31, 1329–1336. [Google Scholar] [CrossRef] [PubMed]
  83. Phosri, S.; Jangpromma, N.; Chang, L.C.; Tan, G.T.; Wongwiwatthananukit, S.; Maijaroen, S.; Anwised, P.; Payoungkiattikun, W.; Klaynongsruang, S. Siamese crocodile white blood cell extract inhibits cell proliferation and promotes autophagy in multiple cancer cell lines. J. Microbiol. Biotechnol. 2018, 28, 1007–1021. [Google Scholar] [CrossRef] [PubMed]
  84. Li, L.; Cheung, H. Turtle shell extract as a functional food and its component-based comparison among different species. Hong Kong Pharm. J. 2012, 19, 33–37. [Google Scholar]
  85. Chen, D.; Yao, W.J.; Zhang, X.L.; Han, X.Q.; Qu, X.Y.; Ka, W.B.; Sun, D.G.; Wu, X.Z.; Wen, W.Y. Effects of Gekko sulfated polysaccharide-protein complex on human hepatoma SMMC-7721 cells: Inhibition of proliferation and migration. J. Ethnopharmacol. 2010, 127, 702–708. [Google Scholar] [CrossRef]
  86. Song, Y.; Wang, J.G.; Li, R.F.; Li, Y.; Cui, Z.C.; Duan, L.X.; Lu, F. Gecko crude peptides induce apoptosis in human liver carcinoma cells in vitro and exert antitumor activity in a mouse ascites H22 xenograft model. J. Biomed. Biotechnol. 2012, 2012, 743573. [Google Scholar] [CrossRef]
  87. Duan, Y.M.; Jin, Y.; Guo, M.L.; Duan, L.X.; Wang, J.G. Differentially expressed genes of HepG2 cells treated with gecko polypeptide mixture. J. Cancer 2018, 9, 2723–2733. [Google Scholar] [CrossRef]
  88. Jeyamogan, S.; Khan, N.A.; Sagathevan, K.; Siddiqui, R. Anticancer properties of Asian water monitor lizard (Varanus salvator), python (Malayophyon reticulatus) and tortoise (Cuora kamaroma amboinensis). Anticancer Agents Med. Chem. 2020, 20, 1558–1570. [Google Scholar] [CrossRef]
  89. Tian, L.; Deng, Y.T.; Dong, X.; Fan, J.Y.; Li, H.L.; Ding, Y.M.; Peng, W.X.; Chen, Q.X.; Shen, D.Y. Siamese crocodile bile induces apoptosis in NCI-H1299 human non-small cell lung cancer cells via a mitochondria-mediated intrinsic pathway and inhibits tumorigenesis. Mol. Med. Rep. 2017, 15, 1727–1737. [Google Scholar] [CrossRef]
  90. Jebali, J.; Fakhfekh, E.; Morgen, M.; Srairi-Abid, N.; Majdoub, J.; Gargour, A.; Ayeb, M.E.; Luis, J.; Marrakchi, N.; Sarray, S. Lebecin, a new C-type lectin like protein from Macrovipera lebetina venom with anti-tumor activity against the breast cancer cell line MDA-MB231. Toxicon 2014, 86, 16–27. [Google Scholar] [CrossRef]
  91. Azevedo, F.V.P.V.; Lopes, D.S.; Gimenes, S.N.C.; Ache, D.C.; Vecchi, L.; Alves, P.T.; Guimaraes, D.O.; Rodrigues, R.S.; Goulart, L.R.; Rodrigues, V.M.; et al. Human breast cancer cell death induced by BnSP-6, a Lys-49 PLA2 homologue from Bothrops pauloensis venom. Int. J. Biol. Macromol. 2016, 82, 671–677. [Google Scholar] [CrossRef] [PubMed]
  92. Attarde, S.S.; Pandit, S.V. Cytotoxic activity of NN-32 toxin from Indian spectacled cobra venom on human breast cancer cell lines. BMC Complement Altern. Med. 2017, 17, 503. [Google Scholar] [CrossRef] [PubMed]
  93. Wang, Y.; Li, K.; Han, S.; Tian, Y.H.; Hu, P.C.; Xu, X.L.; He, Y.Q.; Pan, W.T.; Gao, Y.; Zhang, Z.; et al. Chlorotoxin targets ERα/VaSP signaling pathway to combat breast cancer. Cancer Med. 2019, 8, 1679–1693. [Google Scholar] [CrossRef] [PubMed]
  94. Hammouda, M.B.; Riahi-Chebbi, I.; Souid, S.; Othman, H.; Aloui, Z.; Srairi-Abid, N.; Karou, H.; Gasmi, A.; Magnenat, E.M.; Wells, T.N.C.; et al. Macrovipecetin, a C-type lectin from Macrovipera lebetina venom, inhibits proliferation migration and invasion of SK-MEL-28 human melanoma cells and enhances their sensitivity to cisplatin. Biochim. Biophys. Acta. Gen. Subj. 2018, 1862, 600–614. [Google Scholar] [CrossRef] [PubMed]
  95. Almeida, C.F.; Amaral, C.; Augusto, T.V.; Correia-da-Silva, G.; Andrade, C.M.; Torqueti, M.R.; Teixeira, N. The anti-cancer potential of crotoxin in estrogen receptor-positive breast cancer: Its effects and mechanism of action. Toxicon 2021, 200, 69–77. [Google Scholar] [CrossRef]
  96. Derakhshani, A.; Silverstris, N.; Hajiasgharzadeh, K.; Mahmoudzadeh, S.; Fereidouni, M.; Paradiso, A.V.; Brunetti, O.; Atarod, D.; Safarpour, H.; Baradaran, B. Expression and characterization of a novel recombinant cytotoxin II from Naja naja oxiana venom: A potential treatment for breast cancer. Int. J. Biol. Macromol. 2020, 162, 1283–1292. [Google Scholar] [CrossRef]
  97. Ye, B.; Xie, Y.; Qin, Z.H.; Wu, J.C.; Han, R.; He, J.K. Anti-tumor activity of CrTX in human lung adenocarcinoma cell line A549. Acta Pharmacol. Sin. 2011, 32, 1397–1401. [Google Scholar] [CrossRef]
  98. Pathan, J.; Mondal, S.; Sarkar, A.; Chakrabarty, D. Daboialectin, a C-type lectin from Russell’s viper venom induces cytoskeletal damage and apoptosis in human lung cancer cells in vitro. Toxicon 2017, 127, 11–21. [Google Scholar] [CrossRef]
  99. Liu, Y.; Ming, W.; Wang, Y.; Liu, S.; Qiu, Y.; Xiang, Y.; Hu, L.; Fan, L.; Peng, X.; Wang, H.; et al. Cytotoxin 1 from Naja atra Cantor venom induced necroptosis of leukemia cells. Toxicon 2019, 165, 110–115. [Google Scholar] [CrossRef]
  100. Chernyshenko, V.; Petruk, N.; Korolova, D.; Kasatkina, L.; Gornytska, O.; Platonova, T.; Chernyshenko, T.; Revriev, A.; Dzhus, O.; Garmanchuk, L.; et al. Antiplatelet and anti-proliferative action of disintegrin from Echis multisquamatis snake venom. Croat. Med. J. 2017, 58, 118–127. [Google Scholar] [CrossRef]
  101. Lafnoune, A.; Lee, S.Y.; Heo, J.Y.; Gourja, I.; Darkaoui, B.; Abdelkafi-Koubaa, Z.; Chgoury, F.; Daoudi, K.; Chakir, S.; Cadi, R.; et al. Anti-cancer effect of Moroccan cobra Naja hage venom and its fractions against hepatocellular carcinoma in 3D cell culture. Toxins 2021, 13, 402. [Google Scholar] [CrossRef] [PubMed]
  102. Moridikia, A.; Zargan, J.; Sobati, H.L.; Goodarzi, H.R.; Hajinourmohamadi, A. Anticancer and antibacterial effects of Iranian viper (Vipera latifii) venom; an in-vitro study. J. Cell. Physiol. 2018, 233, 6790–6797. [Google Scholar] [CrossRef] [PubMed]
  103. Mohamed, K.A.; Mostafa, A.A.; Danny, M.R.; Gamal, B. Induction of apoptosis and growth arrest in human breast carcinoma cells by a snake (Walterinnesia aegyptia) venom combined with silica nanoparticles: Crosstalk between Bcl2 and Caspase 3. Cell. Physiol. Biochem. 2012, 30, 653–665. [Google Scholar]
  104. Derakhshani, A.; Silvestris, N.; Hemmat, N.; Asadzadeh, Z.; Shadbad, M.A.; Nourbakhsh, N.S.; Mobasheri, L.; Vahedi, P.; Shahmirzaie, M.; Brunetti, O.; et al. Targeting TGF-β-mediated SMAD signaling pathway via novel recombinant cytotoxin II: A potent protein from Naja naja oxiana venom in melanoma. Molecules 2020, 25, 5148. [Google Scholar] [CrossRef] [PubMed]
  105. Maria, D.A.; Silva, M.G.L.; Junior, M.C.C.; Ruiz, I.R.G. Antiproliferative effect of the jararhagin toxin on B16F10 murine melanoma. BMC Complement Altern. Med. 2014, 14, 446. [Google Scholar] [CrossRef] [PubMed]
  106. Salama, W.H.; Ibrahim, N.M.; Hakim, A.E.E.; Bassuiny, R.I.; Mohamed, M.M.; Mousa, F.M.; Ali, M.M. L-amino acid oxidase from Cerastes vipera snake venom: Isolation, characterization and biological effects on bacteria and tumor cell lines. Toxicon 2018, 150, 270–279. [Google Scholar] [CrossRef]
  107. Lu, W.; Hu, L.; Yang, J.; Sun, X.; Yan, H.; Liu, J.; Chen, J.; Cheng, X.; Zhou, Q.; Yu, Y.; et al. Isolation and pharmacological characterization of a new cytotoxic L-amino acid oxidase from Bungarus multicinctus snake venom. J. Ethnopharmacol. 2018, 213, 311–320. [Google Scholar] [CrossRef]
  108. Mostafa, I.A.; Sanaa, O.A.; Mohamed, A.E.; Mohammad, Y.A.; Serag, E.I.E.; Aly, F.M. Evaluation of the anticancer potential of crude, irradiated Cerastes cerastes snake venom and propolis ethanolic extract & related biological alterations. Molecules 2021, 26, 7057. [Google Scholar]
  109. Uddin, M.B.; Lee, B.H.; Nikapitiya, C.; Kim, J.H.; Kim, T.H.; Lee, H.C.; Kim, C.G.; Lee, J.S.; Kim, C.J. Inhibitory effects of bee venom and its components against viruses in vitro and in vivo. J. Microbiol. 2016, 54, 853–866. [Google Scholar] [CrossRef]
  110. Moreno, M.; Giralt, E. Three valuable peptides from bee and wasp venoms for therapeutic and biotechnological use: Melittin, apamin and mastoparan. Toxins 2015, 7, 1126–1150. [Google Scholar] [CrossRef]
  111. Chalk, C.H.; Benstead, T.J.; Pound, J.D.; Keezer, M.R. Medical treatment for botulism. Cochrane Database Syst. Rev. 2019, 4, CD008123. [Google Scholar] [CrossRef] [PubMed]
  112. Rao, A.K.; Sobel, J.; Chatham-Stephens, K.; Luquez, C. Clinical guidelines for diagnosis and treatment of botulism, 2021. MMWR Recomm. Rep. 2021, 70, 1–30. [Google Scholar] [CrossRef] [PubMed]
  113. Lonati, D.; Schicchi, A.; Crevani, M.; Buscaglia, E.; Scaravaggi, G.; Maida, F.; Cirronis, M.; Petrolini, V.M.; Locatelli, C.A. Foodborne botulism: Clinical diagnosis and medical treatment. Toxins 2020, 12, 509. [Google Scholar] [CrossRef] [PubMed]
  114. Falcao, C.B.; Radis-Baptista, G. Crotamine and crotalicidin, membrane active peptides from Crotalus durissus terrificus rattlesnake venom, and their structurally-minimized fragments for applications in medicine and biotechnology. Peptides 2020, 126, 170234. [Google Scholar] [CrossRef]
  115. Badr, G.; Al-Sadoon, M.K.; Rabah, D.M. Therapeutic efficacy and molecular mechanisms of snake (Walterinnesia aegyptia) venom-loaded silica nanoparticles in the treatment of breast cancer- and prostate cancer-bearing experimental mouse models. Free Radic. Biol. Med. 2013, 65, 175–189. [Google Scholar] [CrossRef]
  116. Badr, G.; Al-Saddon, M.K.; Abdel-Maksoud, M.A.; Rabah, D.M.; El-Toni, A. Cellular and molecular mechanisms underlie the anti-tumor activities exerted by Walterinnesia aegyptia venom combined with silica nanoparticles against multiple myeloma cancer cell types. PLoS ONE 2012, 7, e51661. [Google Scholar] [CrossRef]
  117. Ma, D.L.; Wu, C.; Cheng, S.S.; Lee, J.W.; Han, Q.B.; Leung, C.H. Development of natural product-conjugated metal complexes as cancer therapies. Int. J. Mol. Sci. 2019, 20, 341. [Google Scholar] [CrossRef]
  118. Baker, C.; Rodrigues, T.; Almeida, B.P.; Barbosa-Morais, N.L.; Bernardes, G.J.L. Natural product-drug conjugates for modulation of TRPV1-expressing tumors. Bioorg. Med. Chem. 2019, 27, 2531–2536. [Google Scholar] [CrossRef]
  119. Liang, Y.; Liu, Z.Y.; Wang, P.Y.; Li, Y.J.; Wang, R.R.; Xie, S.Y. Nanoplatform-based natural products co-delivery system to surmount cancer multidrug-resistant. J. Control Release 2021, 336, 396–409. [Google Scholar] [CrossRef]
  120. Worsham, R.D.; Thomas, V.; Farid, S.S. Potential of continuous manufacturing for liposomal drug products. Biotechnol. J. 2019, 14, e1700740. [Google Scholar] [CrossRef]
  121. Billings, C.; Anderson, D.E. Role of implantable drug delivery devise with dual platform capabilities in the prevention and treatment of bacterial osteomyelitis. Bioengineering 2022, 9, 65. [Google Scholar] [CrossRef] [PubMed]
Pharmaceutics 14 00874 g001
Figure 1. Schematic image of anticancer effect mechanisms of reptile-derived components.
Figure 1. Schematic image of anticancer effect mechanisms of reptile-derived components.
Pharmaceutics 14 00874 g001
Table 1. The anticancer effects of representative plant-derived natural products.
Table 1. The anticancer effects of representative plant-derived natural products.
Natural ComponentsSourceType of CancerMechanismRefs.
VincristineCatharanthus roseusAcute lymphocytic leukemia
Acute myeloid leukemia
Hodgkin’s disease
Neuroblastoma
Lung cancer		Induction of apoptosis via binding to β-tubulin during cell division[42]
VinblastineCatharanthus roseusLeukemia
Lymphoma		Induction of apoptosis via microtubule interference during cell division[43]
PaclitaxelTaxus brevifoliaBreast cancer
Kaposi’s sarcoma
Pancreatic cancer
Gastric cancer		Inhibition of mitotic spindle assembly during cell division[44]
ResveratrolRheum rhaponticumLymphoma
Breast cancer		Suppression of Treg cells
Inhibition of TGF-β production
Interference interaction of PD-1/PD-L1		[45]
CurcuminCurcuma longaBreast cancer
Lung cancer
Gastric cancer
Colon cancer		Induction of cell cycle arrest and apoptosis via inhibition of ERK, PI3K/Akt, Notch-1 and STAT-3 [46]
CapsaicinCapsicum annuumOsteosarcomaPromotion of immunogenic cell death by mediating phagocytosis[47]
Epigallocatechin-3-gallate (EGCG)Camelia sinensisProstate cancer
Melanoma		Induction of apoptosis and anti-angiogenesis[48]
ParthenolideTanacetum partheniumBreast cancer
Lung cancer		Inhibition of JAK/STAT signaling
Downregulation of EGFR expression		[49,50]
Ginsenoside Rg3Panax ginsengBreast cancer
Colon cancer
Gastric cancer
Liver cancer		Induction of apoptosis via inhibition of ERK and Akt
Inhibition of proliferation via G1 phase cell cycle arrest		[51]
WogoninScutellaria baicalensisColon cancer
Ovarian cancer		Inhibition of YAP1 expression
Inhibition of VEGF, Bcl-2 and Akt signaling		[52,53]
Table 2. The anticancer effects of representative marine natural products.
Table 2. The anticancer effects of representative marine natural products.
Natural ComponentsSourceType of CancerMechanismRefs.
FucoidanAscophyllum nodosumColon cancer
Breast cancer		Activation of macrophages and NK cells
Induction of G1 phase cell cycle arrest		[54]
TZT-1027 (Soblidotin)Dolabella auriculariaLung cancer
Colon cancer		Anti-angiogenesis
Induction of apoptosis via microtubule interference during cell division		[55,56]
HeparinDictyopteris delicatulaLung cancer
Liver cancer
Cervical cancer		Inhibition of PI3K/Akt signaling
Anti-metastasis		[57,58,59]
SansalvamideFusarium solaniPancreatic cancer
Colon cancer
Prostate cancer
Breast cancer		Induction of apoptosis via G1 phase cell cycle arrest[60,61]
PlitidepsinAplidium albicansChronic lymphocytic leukemiaInhibition of CXCL12 release from nurse-like cells (NLCs)[62]
Dolastatin 10Dolabella auriculariaBreast cancer
Lung cancer
Prostate cancer		Induction of apoptosis via microtubule interference during cell division[63,64]
Halichondrin B (Eribulin)Halichondria okadaiBreast cancer
Liposarcoma		Induction of apoptosis via microtubule interference during cell division[65]
Salinosporamide A (Marizomib)Salinispora tropicaLymphoma
Breast cancer		Induction of apoptosis via inhibition of proteasome activity[66,67,68,69]
C-nucleoside (Cytarabine)Cryptotheca cryptaLeukemiaInhibition of DNA synthesis[70]
Jorumycin (Zalypsis)Jorunna funebrisLeukemia
Lung cancer
Colon cancer		Induction of apoptosis via G1 phase cell cycle arrest[68,71]
Table 3. The anticancer potentials of reptile-derived components.
Table 3. The anticancer potentials of reptile-derived components.
CategoryNatural ComponentsSourceType of CancerMechanismRefs.
ExtractsSulfated polysaccharideGekko swinhonisLiver cancerInhibition of proliferation and differentiation[72]
Aqueous extractsGekko swinhonisLiver cancerInhibition of growth
Reduction in alpha fetoprotein		[73]
PowderGekko japonicusEsophageal carcinoma
Sarcoma		Induction of apoptosis via decrease in VEGF and bFGF expression[74]
Ethanol extractsCyrtopodion scabrumBreast cancer
Colon cancer		Inhibition of growth and migration [75]
Aqueous extractsEublepharis maculariusBladder cancer
Cervical cancer
Lung cancer		Induction of apoptosis via inhibition of PI3K/Akt signaling
Induction of caspase-dependent apoptosis via G2/M phase cell cycle arrest		[76,77,78]
Crocodile cholineCrocodylus siamensisGastric cancerInduction of apoptosis via G2/M phase cell cycle arrest[79]
Methanol extractsCrocodylus palustrisProstate cancerInduction of cell death[80]
Aqueous extracts of white blood cellsCrocodylus siamensisCervical cancerInduction of mitochondria/caspase-3/caspase-9-mediated apoptosis
Inhibition of proliferation, migration and invasion		[81,82]
Aqueous extracts of white blood cellsCrocodylus siamensisLung cancer
Prostate cancer
Breast cancer
Colorectal cancer		Induction of apoptosis via G2/M phase cell cycle arrest[83]
Aqueous extractsChinemys reevesiiLeukemia
Liver cancer		Induction of cell death[84]
Aqueous extractsCuora aurocapitataLeukemia
Liver cancer		Induction of cell death[84]
Aqueous extractsTrachemys scriptaLeukemia
Liver cancer		Induction of cell death[84]
Crude peptidesSulfated polysaccharide–protein complexGekko swinhonisLiver cancerInhibition of proliferation and migration[85]
Alcohol extracted crude peptidesGekko japonicusLiver cancerInduction of apoptosis via Bcl-2/Bax pathway regulation
Reduction in VEGF expression		[86]
Polypeptide mixtureGekko japonicusLiver cancerInduction of apoptosis
Promotion of ROS-related processes and UPR		[87]
SeraBlood serumVaranus salvatorCervical cancer
Prostate cancer
Breast cancer		Induction of cell death[88]
Blood serumMalayopython reticulatusCervical cancer
Prostate cancer
Breast cancer		Induction of cell death[88]
Blood serumCuora amboinensis karamojaCervical cancer
Prostate cancer
Breast cancer		Induction of cell death[88]
Bile juiceCrocodylus siamensisLung cancerInduction of mitochondria/caspase-3/caspase-9-mediated apoptosis[89]
VenomLectinMacrovipera lebetinaBreast cancerInhibition of integrin-mediated attachment and migration[90]
BnSP-6
Lys-49 PLA2		Bothrops pauloensisBreast cancerInduction of apoptosis
Inhibition of adhesion, migration and angiogenesis 		[91]
NN-3Naja naja oxianaBreast cancerInhibition of proliferation[92]
ChlorotoxinLeiurus quinquestriatusBreast cancerInhibition of proliferation, migration and invasion[93]
MacrovipecetinMacrovipera lebetinaMelanomaInhibition of proliferation, migration and invasion[94]
CrotoxinCrotalus durissus terrificusBreast cancerInduction of apoptosis via G2/M phase cell cycle arrest
Inhibition of ERK signaling		[95]
Cytotoxin 2Naja naja oxianaBreast cancer
Lung cancer		Induction of apoptosis via G1 phase cell cycle arrest
Activation of caspase-3 and p38 signaling		[96,97]
DaboialectinDaboia russeliiLung cancerInduction of apoptosis
Inhibition of migration		[98]
Cytotoxin 1Naja atraLeukemiaInduction of necroptosis[99]
DisintegrinEchis multisquamatusCervical cancerInhibition of proliferation[100]
Venom extractsNaja hageLiver cancerInduction of cell death[101]
Venom extractsVipera latifiiLiver cancerInduction of cell death[102]
Venom extractsWalterinnesia aegyptiaBreast cancerInduction of apoptosis
Activation of caspase-3 pathway		[103]
Recombinant protein cytotoxin 2Naja naja oxianaMelanomaInduction of apoptosis via TGF-β-mediating SMAD signaling[104]
JararhaginBothrops jararacaMurine melanomaActivation of caspase-3 pathway
Suppression of tumor growth and metastasis		[105]
L-Amino acid oxidaseCerastes viperaBreast cancer
Liver cancer
Lung cancer
Prostate cancer
Colon cancer		Induction of cell death[106,107]
Irradiated crude venom Cerastes cerastesLung cancer
Prostate cancer		Induction of apoptosis via G2/M phase cell cycle arrest[108]
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Park, S.Y.; Choi, H.; Chung, J.W. Reptiles as Promising Sources of Medicinal Natural Products for Cancer Therapeutic Drugs. Pharmaceutics 2022, 14, 874. https://doi.org/10.3390/pharmaceutics14040874

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Park SY, Choi H, Chung JW. Reptiles as Promising Sources of Medicinal Natural Products for Cancer Therapeutic Drugs. Pharmaceutics. 2022; 14(4):874. https://doi.org/10.3390/pharmaceutics14040874

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Park, Soon Yong, Hyeongrok Choi, and Jin Woong Chung. 2022. "Reptiles as Promising Sources of Medicinal Natural Products for Cancer Therapeutic Drugs" Pharmaceutics 14, no. 4: 874. https://doi.org/10.3390/pharmaceutics14040874

APA Style

Park, S. Y., Choi, H., & Chung, J. W. (2022). Reptiles as Promising Sources of Medicinal Natural Products for Cancer Therapeutic Drugs. Pharmaceutics, 14(4), 874. https://doi.org/10.3390/pharmaceutics14040874

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