Novel Strategies to Improve the Therapeutic Effects of Natural Anticancer Compounds

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biopharmaceutics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 18015

Special Issue Editors


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Guest Editor
Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Powstancow Wlkp. 72 Str., 70-111 Szczecin, Poland
Interests: molecular pharmacology; drug transporters; drug metabolizing enzymes; pharmacogenetics/pharmacogenomics; clinical pharmacology
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Guest Editor
Department of Experimental & Clinical Pharmacology, Pomeranian Medical University, Powstancow Wielkopolskich 72, 70-111 Szczecin, Poland
Interests: nanomaterials biocompatibility; anticancer drug delivery; drug design; mitotic spindle inhibitors

Special Issue Information

It is my pleasure to invite you to contribute research or review articles to a Special Issue entitled “Novel Strategies to Improve the Therapeutic Effects of Natural Anticancer Compounds”. The discovery of cytostatic properties of Vinca alcaloids, taxanes, epipodophyllotoxins, and camptothecin derivatives has revolutionized therapeutic approaches for cancer. Today, in spite of significant advances in cancer therapy related to the application of monoclonal antibodies and specific kinase inhibitors,  natural antimitotic inhibitors remain one of the most widely used drugs in oncology. However, a narrow therapeutic index and the multidrug resistance of those chemotherapeutics determine the search for new potential agents or strategies to improve pharmacotherapy outcomes. Intensive research on the anticancer properties of alkaloids, flavonoids, phenolics, tannins, glycosides, gums, resins, and oils has resulted in the discovery of anticancer properties of many natural compounds, e.g., combretastatin, resveratrol, genistein, curcumin, or berberine. However, in spite of promising experimental results some disadvantages, including poor solubility of hydrophobic compounds, loss of activity at physiological pH, unfavorable pharmacokinetics, or insufficient selectivity against cancer cells have limited their clinical applications.

Thus, new approaches to enhance the bioavailability of natural compounds are needed. Various delivery systems, including liposomes, nanocarriers or biopolymers provide several advantages over traditional formulations: they protect drugs from premature release and degradation, enable a sustained release of therapeutic agents, reduce the need for toxic solvent applications, and allow selective (ligand-dependent) drug transport to cancer cells. Authors are invited to submit papers focused on new strategies for the delivery of natural anticancer compounds (well known or new) contributing to increased anticancer therapy outcomes and decreased side effects.

Prof. Dr. Marek Drozdzik
Dr. Magdalena Peruzynska
Guest Editors

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Keywords

  • natural bioactive compounds
  • natural anticancer compounds
  • plant extracts
  • pharmaceutical vehicles
  • bioavailability
  • biomaterials
  • nanotechnology
  • biopolymers
  • drug release
  • drug delivery systems
  • in vitro study
  • in vivo study

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Published Papers (7 papers)

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Research

18 pages, 4086 KiB  
Article
Licochalcone A Suppresses Renal Cancer Cell Proliferation and Metastasis by Engagement of Sp1-Mediated LC3 Expression
by Tsai-Yi Tseng, Chien-Hsing Lee, Hsiang-Lin Lee, Chien-Yu Su, Cheng-Yen Kao, Jen-Pi Tsai and Yi-Hsien Hsieh
Pharmaceutics 2023, 15(2), 684; https://doi.org/10.3390/pharmaceutics15020684 - 17 Feb 2023
Cited by 4 | Viewed by 1834
Abstract
Licochalcone A (LicA) is a strong anti-inflammatory, antioxidant, and anticarcinogenic substance that is useful against a variety of human malignancies. However, its precise mechanism in mediating the development of renal cell carcinoma (RCC) is not entirely understood. In this work, LicA was discovered [...] Read more.
Licochalcone A (LicA) is a strong anti-inflammatory, antioxidant, and anticarcinogenic substance that is useful against a variety of human malignancies. However, its precise mechanism in mediating the development of renal cell carcinoma (RCC) is not entirely understood. In this work, LicA was discovered to limit cell growth and survival, induce cell cycle arrest, promote autophagy and LC3B expression, and inhibit the migration and invasion of RCC cells. In addition, the proliferation, migration, and invasion inhibited by LicA were restored by the transfection of siRNA-LC3. The effects of LC3B on the metastatic phenotype of ACHN cells was enhanced with the overexpression of Sp1 or suppressed by inhibiting the phosphorylation of FAK and Src. Finally, LicA showed antitumor properties against RCC in an in vivo xenograft model. In conclusion, our study demonstrated the chemotherapeutic potential of LicA on proliferation, migration, invasion, and autophagy through the activation of LC3B expression, ultimately modulating FAK/Src signaling pathway-mediated Sp1 expression. These findings illustrate the novel role and molecular mechanisms of LicA against RCC cells. Full article
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15 pages, 2334 KiB  
Article
Molecular Mechanisms of Inhibitory Effects of Bovine Lactoferrin on Invasion of Oral Squamous Cell Carcinoma
by Chanbora Chea, Mutsumi Miyauchi, Toshihiro Inubushi, Kana Okamoto, Sivmeng Haing and Takashi Takata
Pharmaceutics 2023, 15(2), 562; https://doi.org/10.3390/pharmaceutics15020562 - 7 Feb 2023
Cited by 5 | Viewed by 1674
Abstract
Lactoferrin (LF), an iron-binding glycoprotein, has been reported to have anticancer properties. However, the molecular mechanisms behind its anticancer effects on oral squamous cell carcinoma (OSCC) have not yet been elucidated. Therefore, we aimed to clarify the effects of LF on invasion of [...] Read more.
Lactoferrin (LF), an iron-binding glycoprotein, has been reported to have anticancer properties. However, the molecular mechanisms behind its anticancer effects on oral squamous cell carcinoma (OSCC) have not yet been elucidated. Therefore, we aimed to clarify the effects of LF on invasion of OSCC, and its underlying molecular mechanism. OSCC cell lines, HSC2 and HOC313, were treated with bovine LF (bLF). The effects of bLF on cell invasion were examined by a chamber migration assay, wound healing assay, and Boyden chamber method with a basement-membrane-analogue. Expression levels of MMP-1, MMP-3, and AP-1 were examined using RT-PCR, qRT-PCR, and western blotting. Roles of LRP1, a receptor of bLF, on cell invasion were analyzed using siLRP1 knockdown cells. Furthermore, to clarify the importance of LRP1 in invasion, the effects of bLF on tPA-induced invasion of OSCC cells were examined. The invasion assays showed that bLF suppressed invasion of the OSCC cells. Moreover, bLF down-regulated AP-1, and resulted in reductions of MMP-1 and MMP-3. With SiLRP1 knockdown, OSCC cells failed to induce their invasion, and bLF was not able to exert its effects on invasion. Furthermore, bLF remarkably inhibited tPA-induced cell invasion. These findings suggest the importance of LRP1 in bLF-suppressed invasion of OSCC cells via the reduction of AP-1 and MMP production. Full article
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20 pages, 4451 KiB  
Article
Co-Delivery System of Curcumin and Colchicine Using Functionalized Mesoporous Silica Nanoparticles Promotes Anticancer and Apoptosis Effects
by Khaled AbouAitah, Ahmed A. F. Soliman, Anna Swiderska-Sroda, Amr Nassrallah, Julita Smalc-Koziorowska, Stanislaw Gierlotka and Witold Lojkowski
Pharmaceutics 2022, 14(12), 2770; https://doi.org/10.3390/pharmaceutics14122770 - 11 Dec 2022
Cited by 10 | Viewed by 2712
Abstract
Purpose: Many natural agents have a high anticancer potential, and their combination may be advantageous for improved anticancer effects. Such agents, however, often are not water soluble and do not efficiently target cancer cells, and the kinetics of their action is poorly controlled. [...] Read more.
Purpose: Many natural agents have a high anticancer potential, and their combination may be advantageous for improved anticancer effects. Such agents, however, often are not water soluble and do not efficiently target cancer cells, and the kinetics of their action is poorly controlled. One way to overcome these barriers is to combine natural agents with nanoparticles. Our aim in the current study was to fabricate an anticancer nanoformulation for co-delivery of two natural agents, curcumin (CR) and colchicine (CL), with a core-shell structure. Using cancer cell lines, we compared the anticancer efficacy between the combination and a nanoformulation with CL alone. Methods: For the single-drug nanoformulation, we used phosphonate groups to functionalize mesoporous silica nanoparticles (MSNs) and loaded the MSNs with CL. Additional loading of this nanoformulation with CR achieved the co-delivery format. To create the structure with a core shell, we selected a chitosan–cellulose mixture conjugated with targeting ligands of folic acid for the coating. For evaluating anticancer and apoptosis effects, we assessed changes in important genes and proteins in apoptosis (p53, caspase-3, Bax, Bcl-2) in several cell lines (MCF-7, breast adenocarcinoma; HCT-116, colon carcinoma; HOS, human osteosarcoma; and A-549, non–small cell lung cancer). Results: Nanoformulations were successfully synthesized and contained 10.9 wt.% for the CL single-delivery version and 18.1 wt.% for the CL+CR co-delivery nanoformulation. Anticancer effects depended on treatment, cell line, and concentration. Co-delivery nanoformulations exerted anticancer effects that were significantly superior to those of single delivery or free CL or CR. Anticancer effects by cell line were in the order of HCT-116 > A549 > HOS > MCF-7. The lowest IC50 value was obtained for the nanoformulation consisting of CL and CR coated with a polymeric shell conjugated with FA (equivalent to 4.1 ± 0.05 µg/mL). With dual delivery compared with the free agents, we detected strongly increased p53, caspase-3, and Bax expression, but inhibition of Bcl-2, suggesting promotion of apoptosis. Conclusions: Our findings, although preliminary, indicate that the proposed dual delivery nanoformulation consisting of nanocore: MSNs loaded with CL and CR and coated with a shell of chitosan–cellulose conjugated folic acid exerted strong anticancer and apoptotic effects with potent antitumor activity against HCT-116 colon cells. The effect bested CL alone. Evaluating and confirming the efficacy of co-delivery nanoformulations will require in vivo studies. Full article
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17 pages, 3507 KiB  
Article
Response of Skin-Derived and Metastatic Human Malignant Melanoma Cell Lines to Thymoquinone and Thymoquinone-Loaded Liposomes
by Patrycja Kłos, Magdalena Perużyńska, Magdalena Baśkiewicz-Hałasa, Paulina Skupin-Mrugalska, Małgorzata Majcher, Magdalena Sawczuk, Bartosz Szostak, Marek Droździk, Bogusław Machaliński and Dariusz Chlubek
Pharmaceutics 2022, 14(11), 2309; https://doi.org/10.3390/pharmaceutics14112309 - 27 Oct 2022
Cited by 7 | Viewed by 2483
Abstract
Thymoquinone has been proved to be effective against neoplasms, including skin cancer. Its high lipophilicity, however, may limit its potential use as a drug. Melanoma remains the deadliest of all skin cancers worldwide, due to its high heterogeneity, depending on the stage of [...] Read more.
Thymoquinone has been proved to be effective against neoplasms, including skin cancer. Its high lipophilicity, however, may limit its potential use as a drug. Melanoma remains the deadliest of all skin cancers worldwide, due to its high heterogeneity, depending on the stage of the disease. Our goal was to compare the anti-cancer activity of free thymoquinone and thymoquinone-loaded liposomes on two melanoma cell lines that originated from different stages of this cancer: skin-derived A375 and metastatic WM9. We evaluated the proapoptotic effects of free thymoquinone by flow cytometry and Western blot, and its mitotoxicity by means of JC-1 assay. Additionally, we compared the cytotoxicity of free thymoquinone and thymoquinone in liposomes by WST-1 assay. Our results revealed a higher antiproliferative effect of TQ in WM9 cells, whereas its higher proapoptotic activity was observed in the A375 cell line. Moreover, the thymoquinone-loaded liposome was proved to exert stronger cytotoxic effect on both cell lines studied than free thymoquinone. Differences in the response of melanoma cells derived from different stages of the disease to thymoquinone, as well as their different responses to free and carrier-delivered thymoquinone, are essential for the development of new anti-melanoma therapies. However, further research is required to fully understand them. Full article
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22 pages, 4743 KiB  
Article
Ultrasound Triggers Hypericin Activation Leading to Multifaceted Anticancer Activity
by Federica Foglietta, Roberto Canaparo, Simone Cossari, Patrizia Panzanelli, Franco Dosio and Loredana Serpe
Pharmaceutics 2022, 14(5), 1102; https://doi.org/10.3390/pharmaceutics14051102 - 21 May 2022
Cited by 13 | Viewed by 2454
Abstract
The use of ultrasound (US) in combination with a responsive chemical agent (sonosensitizer) can selectively trigger the agent’s anticancer activity in a process called sonodynamic therapy (SDT). SDT shares some properties with photodynamic therapy (PDT), which has been clinically approved, but sets itself [...] Read more.
The use of ultrasound (US) in combination with a responsive chemical agent (sonosensitizer) can selectively trigger the agent’s anticancer activity in a process called sonodynamic therapy (SDT). SDT shares some properties with photodynamic therapy (PDT), which has been clinically approved, but sets itself apart because of its use of US rather than light to achieve better tissue penetration. SDT provides anticancer effects mainly via the sonosensitizer-mediated generation of reactive oxygen species (ROS), although the precise nature of the underpinning mechanism is still under debate. This work investigates the SDT anticancer activity of hypericin (Hyp) in vitro in two- (2D) and three-dimensional (3D) HT-29 colon cancer models, and uses PDT as a yardstick due to its well-known Hyp phototoxicity. The cancer cell uptake and cellular localization of Hyp were investigated first to determine the proper noncytotoxic concentration and incubation time of Hyp for SDT. Furthermore, ROS production, cell proliferation, and cell death were evaluated after Hyp was exposed to US. Since cancer relapse and transporter-mediated multidrug resistance (MDR) are important causes of cancer treatment failure, the US-mediated ability of Hyp to elicit immunogenic cell death (ICD) and overcome MDR was also investigated. SDT showed strong ROS-mediated anticancer activity 48 h after treatment in both the HT-29 models. Specific damage-associated molecular patterns that are consistent with ICD, such as calreticulin (CRT) exposure and high-mobility group box 1 protein (HMGB1) release, were observed after SDT with Hyp. Moreover, the expression of the ABC transporter, P-glycoprotein (P-gp), in HT-29/MDR cells was not able to hinder cancer cell responsiveness to SDT with Hyp. This work reveals, for the first time, the US responsiveness of Hyp with significant anticancer activity being displayed, making it a full-fledged sonosensitizer for the SDT of cancer. Full article
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27 pages, 3770 KiB  
Article
Anti-Cancerous Potential of Polysaccharides Derived from Wheat Cell Culture
by Alima Murtazina, Gloria Ruiz Alcala, Yaiza Jimenez-Martinez, Juan Antonio Marchal, Anel Tarabayeva, Elmira Bitanova, Gordon McDougall, Nazira Bishimbayeva and Houria Boulaiz
Pharmaceutics 2022, 14(5), 1100; https://doi.org/10.3390/pharmaceutics14051100 - 20 May 2022
Cited by 5 | Viewed by 2769
Abstract
There is a global need to discover effective anti-cancerous compounds from natural sources. Cultivated wheat cells can be a valuable source of non-toxic or low toxic plant-derived polysaccharides. In this study, we evaluated the anti-cancer ability of seven fractions of wheat cell culture [...] Read more.
There is a global need to discover effective anti-cancerous compounds from natural sources. Cultivated wheat cells can be a valuable source of non-toxic or low toxic plant-derived polysaccharides. In this study, we evaluated the anti-cancer ability of seven fractions of wheat cell culture polysaccharides (WCCPSs) in the HCT-116 colon cancer cell line. Almost all (6/7) fractions had an inhibitory effect on the proliferation of colon cancer cells, and two fractions (A-b and A-f) had considerable therapeutic indexes. The WCCPS fractions induced cell cycle arrest in the G1 phase and induced different rates of apoptosis (≤48%). Transmission and scanning electron microscopy revealed that WCCPS fractions caused apoptotic changes in the nucleus and cytoplasm, including damage to mitochondria and external morphological signs of apoptosis. In addition, the WCCPSs induced an increase in the levels of Bax, cytochrome c, and caspases 8 and 3, indicating that cell death progressed through intrinsic and extrinsic pathways of apoptosis. Furthermore, some fractions caused a significant decrease of c-Myc, b-catenin, NFkB2, and HCAM (CD 44) levels, indicating enhanced cell differentiation. Thus, for the first time, our results provide a proof of concept of the anti-cancer capacity of WCCPS fractions in colorectal cancer. Full article
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22 pages, 5099 KiB  
Article
Timosaponin A3 Inhibits Palmitate and Stearate through Suppression of SREBP-1 in Pancreatic Cancer
by Yumi Kim, Wona Jee, Eun-Jin An, Hyun Min Ko, Ji Hoon Jung, Yun-Cheol Na and Hyeung-Jin Jang
Pharmaceutics 2022, 14(5), 945; https://doi.org/10.3390/pharmaceutics14050945 - 27 Apr 2022
Cited by 8 | Viewed by 2837
Abstract
Timosaponin A3 (TA3) was demonstrated as a potent anticancer chemical by several studies. Although the effects of inhibiting growth, metastasis, and angiogenesis in various cancer cells were demonstrated through multiple mechanisms, the pharmacological mechanism of TA3 shown in pancreatic cancer (PC) is insufficient [...] Read more.
Timosaponin A3 (TA3) was demonstrated as a potent anticancer chemical by several studies. Although the effects of inhibiting growth, metastasis, and angiogenesis in various cancer cells were demonstrated through multiple mechanisms, the pharmacological mechanism of TA3 shown in pancreatic cancer (PC) is insufficient compared to other cancers. In this study, we aimed to explore the key molecular mechanisms underlying the growth inhibitory effects of TA3 using PC cells and a xenograft model. First, from the microarray results, we found that TA3 regulated INSIG-1 and HMGCR in BxPC-3 cells. Furthermore, we showed that inhibition of sterol regulatory element-binding protein-1 (SREBP-1) by TA3 reduced the fatty acid synthases FASN and ACC, thereby controlling the growth of BxPC-3 cells. We also tried to find mechanisms involved with SREBP-1, such as Akt, Gsk3β, mTOR, and AMPK, but these were not related to SREBP-1 inhibition by TA3. In the BxPC-3 xenograft model, the TA3 group had more reduced tumor formation and lower toxicity than the gemcitabine group. Interestingly, the level of the fatty acid metabolites palmitate and stearate were significantly reduced in the tumor tissue in the TA3 group. Overall, our study demonstrated that SREBP-1 was a key transcription factor involved in pancreatic cancer growth and it remained a precursor form due to TA3, reducing the adipogenesis and growth in BxPC-3 cells. Our results improve our understanding of novel mechanisms of TA3 for the regulation of lipogenesis and provide a new approach to the prevention and treatment of PC. Full article
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