Nature has always been a precious source of bioactive molecules which are used for the treatment of various diseases [1]. Natural compounds such as dietary phytochemicals, nutritional herbs, and their constitutive bioactive agents possess a great variety of chemical scaffolds and distinct bioactivity profiles, which make them suitable for applications in therapy or as valuable lead compounds to obtain novel potent bioactive compounds [2]. Significant advances in natural source isolation and extraction techniques have led to the identification of novel compounds as useful starting points for the generation of optimized molecules with enhanced therapeutic potential via semi-synthetic or synthetic processes [3].
The application of natural products in the field of chemotherapy and chemoprevention is a valuable research topic, leading to the extensive use of plant-derived compounds as potent antitumor molecules [4]. In addition, marine-based pharmaceuticals have been extensively studied for their applications in the anticancer field, providing useful compounds such as cytarabine and trabectedin [5]. Alternative treatments in complement with traditional methods (radiotherapy, chemotherapy, and surgery) have been shown to be helpful and offer very reasonable alternatives to current medicines for cancer [6]. Much effort has also been directed towards the discovery of novel targets [7,8,9] in an attempt to obtain anticancer effects via multiple mechanisms, overcoming the resistance phenomena developed by most cancers.
Natural products effectively inhibit cell proliferation, regulate the cell cycle, and interfere with several tumorigenic signaling pathways [10,11]. The anticancer properties of polyphenols, found abundantly in plants, as flavonoids [12], terpenoids [13], and alkaloids [14], have been extensively reported [15]. However, important research efforts are necessary to fully understand the mechanisms of action of natural compounds by which these agents affect cell proliferation, differentiation, apoptosis, angiogenesis, and metastasis; in addition, there is a need to overcome major problems such as toxicity, poor selectivity, and unfavorable pharmacokinetics [16].
Currently, many plant-based antitumor drugs are in clinical use, such as taxanes, vinblastine, vincristine, and podophyllotoxin analogues. The combined use of phytochemicals like resveratrol, curcumin, and thymoquinone with other antitumor agents has shown significant success in preclinical studies, allowing enhanced efficacy and mitigation of side effects [17,18]. Emerging nanotechnology applications for anticancer drug formulations have been revolutionizing cancer therapy. Tissue-specific nanomedicines play a key role in advanced cancer diagnostic techniques by using liposomes, micelles, and nanoparticles as effective delivery vehicles [19]. Moreover, medicinal plant extracts have proven most effective in various cancers, paving the way for developing novel therapeutic strategies [20]. Many studies have been based on crude aqueous and ethanol extracts, with few explorations of their mechanisms [21].
In this Topic, 30 original articles and 3 reviews have been collected, with a particular focus on the isolation of bioactive compounds from natural sources, the mechanisms of action of anticancer compounds at the cellular level, and the application of active molecules against a panel of solid and hematological cancers, including melanoma, breast, lung, colorectal, prostate, bladder, and gastric cancer. Most of the analyzed compounds were from natural sources, whereas some semi-synthetic derivatives were also identified and discussed.
The most recent findings on the effects of extracts and their constituents in treating various cancers are discussed. Most works focus on the effect of water or ethanolic extracts from natural plants or fungi, such as Viscum album var. coloratum, Drimia Maritima, Trichosanthes, Lupinus albus, Bryopsis plumosa, Elephantus scaber L., Paejangsan, Coix Seed, Lupinus albus, Ocimum sanctum Linn., Euphorbia fischeriana, Moldavian dragonhead, Streptomyces ardesiacus, Cichorium intybus, and Trichosanthes.
The extracts and the isolated components have proven effective against breast, colorectal, lung, bladder, myeloma, and prostate cancer through several mechanisms, including decreased tumor cell viability, modulation of cytokines, secretion of chemokines, modulation of ROS, reduction of specific MMP subtypes, apoptosis, cell cycle inhibition, or by downregulating MAPK.
Table 1 schematically illustrates the content of this Topic, with all the contributions published in the six participating journals.
Table 1.
Original articles and reviews collected in the six journals participating in the Topic.
| Title | Author | Journal | Year | DOI |
|---|---|---|---|---|
| Fermented Mangosteen (Garcinia mangostana L.) Supplementation in the Prevention of HPV-Induced Cervical Cancer: From Mechanisms to Clinical Outcomes | Kharaeva, Z. | Cancers | 2022 | https://doi.org/10.3390/cancers14194707 |
| Scabertopin Derived from Elephantopus scaber L. Mediates Necroptosis by Inducing Reactive Oxygen Species Production in Bladder Cancer In Vitro | Gao, Y. | Cancers | 2022 | https://doi.org/10.3390/cancers14235976 |
| Therapeutic Potential of Deflamin against Colorectal Cancer Development and Progression | Silva, S. | Cancers | 2022 | https://doi.org/10.3390/cancers14246182 |
| Design, Synthesis and Biological Evaluation of Neocryptolepine Derivatives as Potential Anti-Gastric Cancer Agents | Ma, Y. | IJMS | 2022 | https://doi.org/10.3390/ijms231911924 |
| FOXO1 Is a Key Mediator of Glucocorticoid-Induced Expression of Tristetraprolin in MDA-MB-231 Breast Cancer Cells | Jeon, D. | IJMS | 2022 | https://doi.org/10.3390/ijms232213673 |
| New Angucycline Glycosides from a Marine-Derived Bacterium Streptomyces ardesiacus | Anh, C. | IJMS | 2022 | https://doi.org/10.3390/ijms232213779 |
| Flavones, Flavonols, Lignans, and Caffeic Acid Derivatives from Dracocephalum moldavica and Their In Vitro Effects on Multiple Myeloma and Acute Myeloid Leukemia | Jöhrer, K. | IJMS | 2022 | https://doi.org/10.3390/ijms232214219 |
| Anti-Cancer Effects of a New Herbal Medicine PSY by Inhibiting the STAT3 Signaling Pathway in Colorectal Cancer Cells and Its Phytochemical Analysis | Han, S. | IJMS | 2022 | https://doi.org/10.3390/ijms232314826 |
| Combination Therapy of Curcumin and Disulfiram Synergistically Inhibits the Growth of B16-F10 Melanoma Cells by Inducing Oxidative Stress | Fontes, S. | Biomolecules | 2022 | https://doi.org/10.3390/biom12111600 |
| Efficient Synthesis for Altering Side Chain Length on Cannabinoid Molecules and Their Effects in Chemotherapy and Chemotherapeutic Induced Neuropathic Pain | Raup-Konsavage, W. | Biomolecules | 2022 | https://doi.org/10.3390/biom12121869 |
| Ent-Abietane Diterpenoids from Euphorbia fischeriana and Their Cytotoxic Activities | Zhu, Q-F. | Molecules | 2022 | https://doi.org/10.3390/molecules27217258 |
| Lactucin, a Bitter Sesquiterpene from Cichorium intybus, Inhibits Cancer Cell Proliferation by Downregulating the MAPK and Central Carbon Metabolism Pathway | Imam, K. | Molecules | 2022 | https://doi.org/10.3390/molecules27217358 |
| Anticancer Activity of Mannose-Specific Lectin, BPL2, from Marine Green Alga Bryopsis plumosa | Lee, J. | Marine Drugs | 2022 | https://doi.org/10.3390/md20120776 |
| Ethanolic Extract of Ocimum sanctum Linn. Inhibits Cell Migration of Human Lung Adenocarcinoma Cells (A549) by Downregulation of Integrin αvβ3, α5β1, and VEGF | Kustiati, U. | Scientia Pharmaceutica | 2022 | https://doi.org/10.3390/scipharm90040069 |
| Libertellenone T, a Novel Compound Isolated from Endolichenic Fungus, Induces G2/M Phase Arrest, Apoptosis, and Autophagy by Activating the ROS/JNK Pathway in Colorectal Cancer Cells | Gamage, C. | Cancers | 2023 | https://doi.org/10.3390/cancers15020489 |
| New Affordable Methods for Large-Scale Isolation of Major Olive Secoiridoids and Systematic Comparative Study of Their Antiproliferative/Cytotoxic Effect on Multiple Cancer Cell Lines of Different Cancer Origins | Papakonstantinou, A. | IJMS | 2023 | https://doi.org/10.3390/ijms24010003 |
| Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9′ Derivatisation | Paulin, E. | IJMS | 2023 | https://doi.org/10.3390/ijms24021167 |
| Trichosanthin Promotes Anti-Tumor Immunity through Mediating Chemokines and Granzyme B Secretion in Hepatocellular Carcinoma | Wang, K. | IJMS | 2023 | https://doi.org/10.3390/ijms24021416 |
| Camptothecin Effectively Regulates Germline Differentiation through Bam-Cyclin A Axis in Drosophila melanogaster | Zhang, J. | IJMS | 2023 | https://doi.org/10.3390/ijms24021617 |
| JI017 Induces Cell Autophagy and Apoptosis via Elevated Levels of Reactive Oxygen Species in Human Lung Cancer Cells | Ku, J. | IJMS | 2023 | https://doi.org/10.3390/ijms24087528 |
| α-Tocotrienol and Redox-Silent Analogs of Vitamin E Enhances Bortezomib Sensitivity in Solid Cancer Cells through Modulation of NFE2L1 | Ishii, K. | IJMS | 2023 | https://doi.org/10.3390/ijms24119382 |
| Modulation of the Endomembrane System by the Anticancer Natural Product Superstolide/ZJ-101 | Sanchez, P. | IJMS | 2023 | https://doi.org/10.3390/ijms24119575 |
| Mitochondria-Targeting 1,5-Diazacyclooctane-Spacered Triterpene Rhodamine Conjugates Exhibit Cytotoxicity at Sub-Nanomolar Concentration against Breast Cancer Cells | Heise, N. | IJMS | 2023 | https://doi.org/10.3390/ijms241310695 |
| Phytochemical Analysis and Anticancer Properties of Drimia maritima Bulb Extracts on Colorectal Cancer Cells | Al-Abdallat, K. | Molecules | 2023 | https://doi.org/10.3390/molecules28031215 |
| Synthesis of Oleanolic Acid-Dithiocarbamate Conjugates and Evaluation of Their Broad-Spectrum Antitumor Activities | Tang, L. | Molecules | 2023 | https://doi.org/10.3390/molecules28031414 |
| Genistein Inhibits Proliferation and Metastasis in Human Cervical Cancer Cells through the Focal Adhesion Kinase Signaling Pathway: A Network Pharmacology-Based In Vitro Study in HeLa Cells | Chen, T. | Molecules | 2023 | https://doi.org/10.3390/molecules28041919 |
| Anti-Proliferative and Pro-Apoptotic vLMW Fucoidan Formulas Decrease PD-L1 Surface Expression in EBV Latency III and DLBCL Tumoral B-Cells by Decreasing Actin Network | Saliba, J. | Marine Drugs | 2023 | https://doi.org/10.3390/md21020132 |
| A Novel Aldisine Derivative Exhibits Potential Antitumor Effects by Targeting JAK/STAT3 Signaling | Wang, D.-P. | Marine Drugs | 2023 | https://doi.org/10.3390/md21040218 |
| Light-Mediated Transformation of Renieramycins and Semisynthesis of 4′-Pyridinecarbonyl-Substituted Renieramycin-Type Derivatives as Potential Cytotoxic Agents against Non-Small-Cell Lung Cancer Cells | Sinsook, S. | Marine Drugs | 2023 | https://doi.org/10.3390/md21070400 |
| Immuno-Modulatory Effects of Korean Mistletoe in MDA-MB-231 Breast Cancer Cells and THP-1 Macrophages | Lim, W.-T. | Scientia Pharmaceutica | 2023 | https://doi.org/10.3390/scipharm91040048 |
| Molecular Mechanism of Tanshinone against Prostate Cancer | Li, W. | Molecules | 2022 | https://doi.org/10.3390/molecules27175594 |
| Can Natural Products Targeting EMT Serve as the Future Anticancer Therapeutics? | Anwar, S. | Molecules | 2022 | https://doi.org/10.3390/molecules27227668 |
| Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells | Afrin, F. | Cancers | 2023 | https://doi.org/10.3390/cancers15184645 |
Author Contributions
Writing—review and editing, B.D.F., M.F. and A.A. All authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
References
- 1.Cragg G.M., Newman D.J. Natural products: A continuing source of novel drug leads. Biochim. Biophys. Acta. 2013;1830:3670–3695. doi: 10.1016/j.bbagen.2013.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Atanasov A.G., Zotchev S.B., Dirsch V.M., the International Natural Product Sciences Taskforce. Supuran C.T. Natural products in drug discovery: Advances and opportunities. Nat. Rev. Drug Discov. 2021;20:200–216. doi: 10.1038/s41573-020-00114-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Astrain-Redin N., Sanmartin C., Sharma A.K., Plano D. From Natural Sources to Synthetic Derivatives: The Allyl Motif as a Powerful Tool for Fragment-Based Design in Cancer Treatment. J. Med. Chem. 2023;66:3703–3731. doi: 10.1021/acs.jmedchem.2c01406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Naeem A., Hu P., Yang M., Zhang J., Liu Y., Zhu W., Zheng Q. Natural Products as Anticancer Agents: Current Status and Future Perspectives. Molecules. 2022;27:8367. doi: 10.3390/molecules27238367. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Nigam M., Suleria H.A.R., Farzaei M.H., Mishra A.P. Marine anticancer drugs and their relevant targets: A treasure from the ocean. Daru. 2019;27:491–515. doi: 10.1007/s40199-019-00273-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Lin S.R., Chang C.H., Hsu C.F., Tsai M.J., Cheng H., Leong M.K., Sung P.J., Chen J.C., Weng C.F. Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence. Br. J. Pharmacol. 2020;177:1409–1423. doi: 10.1111/bph.14816. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Zhong L., Li Y., Xiong L., Wang W., Wu M., Yuan T., Yang W., Tian C., Miao Z., Wang T., et al. Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives. Signal Transduct. Target. Ther. 2021;6:201. doi: 10.1038/s41392-021-00572-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Franzese O., Graziani G. Role of PARP Inhibitors in Cancer Immunotherapy: Potential Friends to Immune Activating Molecules and Foes to Immune Checkpoints. Cancers. 2022;14:5633. doi: 10.3390/cancers14225633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ammazzalorso A., Agamennone M., De Filippis B., Fantacuzzi M. Development of CDK4/6 Inhibitors: A Five Years Update. Molecules. 2021;26:1488. doi: 10.3390/molecules26051488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Li W., Chen H., Xu B., Wang Y., Zhang C., Cao Y., Xing X. Research progress on classification, sources and functions of dietary polyphenols for prevention and treatment of chronic diseases. J. Future Foods. 2023;3:289–305. doi: 10.1016/j.jfutfo.2023.03.001. [DOI] [Google Scholar]
- 11.Memarzia A., Saadat S., Asgharzadeh F., Behrouz S., Folkerts G., Boskabady M.H. Therapeutic effects of medicinal plants and their constituents on lung cancer, in vitro, in vivo and clinical evidence. J. Cell Mol. Med. 2023;27:2841–2863. doi: 10.1111/jcmm.17936. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Dhyani P., Quispe C., Sharma E., Bahukhandi A., Sati P., Attri D.C., Szopa A., Sharifi-Rad J., Docea A.O., Mardare I., et al. Anticancer potential of alkaloids: A key emphasis to colchicine, vinblastine, vincristine, vindesine, vinorelbine and vincamine. Cancer Cell Int. 2022;22:206. doi: 10.1186/s12935-022-02624-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Fantacuzzi M., Gallorini M., Gambacorta N., Ammazzalorso A., Aturki Z., Balaha M., Carradori S., Giampietro L., Maccallini C., Cataldi A., et al. Design, Synthesis and Biological Evaluation of Aromatase Inhibitors Based on Sulfonates and Sulfonamides of Resveratrol. Pharmaceuticals. 2021;14:984. doi: 10.3390/ph14100984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Kopustinskiene D.M., Jakstas V., Savickas A., Bernatoniene J. Flavonoids as Anticancer Agents. Nutrients. 2020;12:457. doi: 10.3390/nu12020457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Gozari M., Alborz M., El-Seedi H.R., Jassbi A.R. Chemistry, biosynthesis and biological activity of terpenoids and meroterpenoids in bacteria and fungi isolated from different marine habitats. Eur. J. Med. Chem. 2021;210:112957. doi: 10.1016/j.ejmech.2020.112957. [DOI] [PubMed] [Google Scholar]
- 16.Estrela J.M., Mena S., Obrador E., Benlloch M., Castellano G., Salvador R., Dellinger R.W. Polyphenolic phytochemicals in cancer prevention and therapy: Bioavailability versus bioefficacy. J. Med. Chem. 2017;60:9413–9436. doi: 10.1021/acs.jmedchem.6b01026. [DOI] [PubMed] [Google Scholar]
- 17.Blanco-Vaca F., Cedó L., Julve J. Phytosterols in Cancer: From Molecular Mechanisms to Preventive and Therapeutic Potentials. Curr. Med. Chem. 2019;26:6735–6749. doi: 10.2174/0929867325666180607093111. [DOI] [PubMed] [Google Scholar]
- 18.De Filippis B., De Lellis L., Florio R., Ammazzalorso A., Amoia P., Fantacuzzi M., Giampietro L., Maccallini C., Amoroso R., Veschi S., et al. Synthesis and cytotoxic effects on pancreatic cancer cells of resveratrol analogs. Med. Chem. Res. 2019;28:984–991. doi: 10.1007/s00044-019-02351-3. [DOI] [Google Scholar]
- 19.Dhupal M., Chowdhury D. Phytochemical-Based Nanomedicine for Advanced Cancer Theranostics: Perspectives on Clinical Trials to Clinical Use. Int. J. Nanomed. 2020;15:9125–9157. doi: 10.2147/IJN.S259628. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Greenwell M., Rahman P.K. Medicinal Plants: Their Use in Anticancer Treatment. Int. J. Pharm. Sci. Res. 2015;6:4103–4112. doi: 10.13040/IJPSR.0975-8232.6(10).4103-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Radošević K., Ćurko N., Gaurina Srček V., Cvjetko Bubalo M., Tomašević M., Kovačević Ganić K., Radojčić Redovniković I. Natural deep eutectic solvents as beneficial extractants for enhancement of plant extracts bioactivity. LWT. 2016;73:45–51. doi: 10.1016/j.lwt.2016.05.037. [DOI] [Google Scholar]