Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application
Abstract
:1. Introduction
2. Secondary Metabolites from Plants as Anticancer Agents
2.1. Metabolites Used in Cancer Therapy
2.1.1. Vincristine
2.1.2. Paclitaxel
2.1.3. Homoharringtonine
2.2. Metabolites in Clinical Trials
2.2.1. Ingenol Mebutate
2.2.2. Curcumin
2.2.3. Betulinic Acid
3. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
5-FU | 5-fluorouracil |
A2780 | human ovarian carcinoma cell line |
ABCB1 | ATP binding cassette subfamily B member 1 |
ABCC10 | ATP binding cassette subfamily C member 10 |
Akt | serine/threonine-specific protein kinase |
b.w. | body weight |
Bak | pro-apoptotic Bcl-2 protein |
Bax | bcl-2-like protein 4 |
Bcl-2 | B-cell lymphoma 2 protein |
BCR-ABL1 | breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog 1 |
CDKI | cyclin-dependent kinase inhibitors |
colon 205 | human Caucasian colon adenocarcinoma cell line |
CoMFA | comparative molecular field analysis |
CoMSIA | comparative molecular similarity index analysis |
CYP | cytochrome P450 |
DNA | deoxyribonucleic acid |
EMA | European Medicines Agency |
ERK | extracellular signal-regulated kinases |
FAO | Food And Agriculture Organization |
FDA | Food And Drug Administration |
FGF | fibroblast growth factor |
FLT3-ITD | fms-related tyrosine kinase 3 internal tandem duplication |
HIF-1α | hypoxia-inducible factor 1-alpha |
HMGB1 | high mobility group box 1 protein |
IC50 | half maximal inhibitory concentration |
MAPK | mitogen-activated protein kinase |
Mcl-1 | induced myeloid leukemia cell differentiation protein |
MDR | multidrug resistance |
miRNA | micro-ribonucleic acid |
MMP | matrix metalloproteinase |
mRNA | messenger ribonucleic acid |
Myc | proto-oncogene |
nab-paclitaxel | nanoparticle albumin-bound paclitaxel |
NF-κB | nuclear factor kappa B cells |
Nrf2 | nuclear factor (erythroid-derived 2)-like 2 |
P-388 | bipotential murine pre-B cell lymphoma |
PEP005 | ingenol mebutate |
PGDF | platelet-derived growth factor |
P-gp | p-glycoprotein |
PI3K | phosphatidylinositol-4,5-bisphosphate 3-kinase |
PICN | paclitaxel injection concentrate for nanodispersion |
PKC | protein kinase C |
PKCα | protein kinase C-α |
PKCδ | protein kinase C-δ |
QSAR | quantitative structure activity relationship |
RAID | rapid access to intervention in development |
SAR | structure activity relationship |
SCD-1 | stearoyl-CoA- desaturase 1 |
SCLC | small-cell lung cancer |
SIRT1 | NAD-dependent protein deacetylase sirtuin-1 |
SM/Chol | sphingomyelin/cholesterol |
smad3 | mothers against decapentaplegic homolog 3 |
Sp1 | specificity protein 1 |
STAT3 | signal transducer and activator of transcription 3 |
T315I | mutation resulting in an amino acid substitution at position 315 in BCR-ABL1, from a threonine (T) to an isoleucine (I). |
TGF-β | transforming growth factor beta |
TRAIL | tumor necrosis factor-related apoptosis-inducing ligand |
tRNA | transfer ribonucleic acid |
uPAR | urokinase receptor |
VEGF | vascular endothelial growth factor |
WHO | World Health Organization |
References
- Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 2015, 136, 359–386. [Google Scholar] [CrossRef] [PubMed]
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin. 2016, 66, 7–30. [Google Scholar] [CrossRef] [PubMed]
- World Health Organization. Cancer: Fact Sheets; WHO: Geneva, Switzerland, 2017. Available online: http://www.who.int/mediacentre/factsheets/fs297/en/ (accessed on 2 October 2017).
- Bray, F. Transitions in human development and the global cancer burden. In World Cancer Report 2014; Stewart, B.W., Wild, C.P., Eds.; International Agency for Research on Cancer: Lyon, France, 2014; pp. 54–68. ISBN 978-92-832-0443-5. [Google Scholar]
- Adeloye, D.; David, R.A.; Aderemi, A.V.; Iseolorunkanmi, A.; Oyedokun, A.; Iweala, E.E.; Omoregbe, N.; Ayo, C.K. An estimate of the incidence of prostate cancer in Africa: A systematic review and meta-analysis. PLoS ONE 2016, 11, e0153496. [Google Scholar] [CrossRef] [PubMed]
- Alves-Silva, J.M.; Romane, A.; Efferth, T.; Salgueiro, L. North African medicinal plants traditionally used in cancer therapy. Front. Pharmacol. 2017, 8, 1–24. [Google Scholar] [CrossRef] [PubMed]
- Tariq, A.; Sadia, S.; Pan, K.; Ullah, I.; Mussarat, S.; Sun, F.; Abiodun, O.O.; Batbaatar, A.; Li, Z.; Song, D.; et al. A systematic review on ethnomedicines of anticancer plants. Phytother. Res. 2017, 31, 202–264. [Google Scholar] [CrossRef] [PubMed]
- Oyebode, O.; Kandala, N.-B.; Chilton, P.J.; Lilford, R.J. Use of traditional medicine in middle-income countries: A WHO-SAGE study. Health Policy Plan. 2016, 31, 984–991. [Google Scholar] [CrossRef] [PubMed]
- Diorio, C.; Salena, K.; Ladas, E.J.; Lam, C.G.; Afungcwhi, G.M.; Njuguna, F.; Marjerrison, S. Traditional and complementary medicine used with curative intent in childhood cancer: A systematic review. Pediatr. Blood Cancer 2017, 64, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Ma, L.; Wang, B.; Long, Y.; Li, H. Effect of traditional Chinese medicine combined with Western therapy on primary hepatic carcinoma: A systematic review with meta-analysis. Front. Med. 2017, 11, 191–202. [Google Scholar] [CrossRef] [PubMed]
- Yan, Z.; Lai, Z.; Lin, J. Anticancer properties of traditional Chinese medicine. Comb. Chem. High Throughput Screen. 2017, 20, 423–429. [Google Scholar] [CrossRef] [PubMed]
- Enioutina, E.Y.; Salis, E.R.; Job, K.M.; Gubarev, M.I.; Krepkova, L.V.; Sherwin, C.M. Herbal Medicines: Challenges in the modern world. Part 5. Status and current directions of complementary and alternative herbal medicine worldwide. Expert Rev. Clin. Pharmacol. 2017, 10, 327–338. [Google Scholar] [CrossRef] [PubMed]
- Mishra, B.B.; Tiwari, V.K. Natural products: An evolving role in future drug discovery. Eur. J. Med. Chem. 2011, 46, 4769–4807. [Google Scholar] [CrossRef] [PubMed]
- Gali-Muhtasib, H.; Hmadi, R.; Kareh, M.; Tohme, R.; Darwiche, N. Cell death mechanisms of plant-derived anticancer drugs: Beyond apoptosis. Apoptosis 2015, 20, 1531–1562. [Google Scholar] [CrossRef] [PubMed]
- Khalid, E.B.; Ayman, E.E.; Rahman, H.; Abdelkarim, G.; Najda, A. Natural products against cancer angiogenesis. Tumor Biol. 2016, 37, 14513–14536. [Google Scholar] [CrossRef] [PubMed]
- Katz, L.; Baltz, R.H. Natural product discovery: Past, present and future. J. Ind. Microbiol. Biotechnol. 2016, 43, 155–176. [Google Scholar] [CrossRef] [PubMed]
- Kotoku, N.; Arai, M.; Kobayashi, M. Search for anti-angiogenic substances from natural sources. Chem. Pharm. Bull. 2016, 64, 128–134. [Google Scholar] [CrossRef] [PubMed]
- Bernardini, S.; Tiezzi, A.; Laghezza Masci, V.; Ovidi, E. Natural products for human health: An historical overview of the drug discovery approaches. Nat. Prod. Res. 2017. [Google Scholar] [CrossRef] [PubMed]
- 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] [PubMed]
- Ekor, M. The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety. Front. Pharmacol. 2014, 4, 1–10. [Google Scholar] [CrossRef] [PubMed]
- Moreira, D.L.; Teixeira, S.S.; Monteiro, M.H.D.; de-Oliveira, A.C.A.X.; Paumgartten, F.J.R. Traditional use and safety of herbal medicines. Rev. Bras. Farmacogn. 2014, 24, 248–257. [Google Scholar] [CrossRef]
- Nwodo, J.N.; Ibezim, A.; Simoben, C.V.; Ntie-Kang, F. Exploring cancer therapeutics with natural products from African medicinal plants, Part II: Alkaloids, terpenoids and flavonoids. Anticancer Agents Med. Chem. 2016, 16, 108–127. [Google Scholar] [CrossRef] [PubMed]
- Habli, Z.; Toumieh, G.; Fatfat, M.; Rahal, O.N.; Gali-Muhtasib, H. Emerging cytotoxic alkaloids in the battle against cancer: Overview of molecular mechanisms. Molecules 2017, 22, 250. [Google Scholar] [CrossRef] [PubMed]
- Delgoda, R.; Murray, J.E. Evolutionary perspectives on the role of plant secondary metabolites. In Pharmacognosy: Fundamentals, Applications and Strategies, 1st ed.; Badal, S., Delgoda, R., Eds.; Academic Press: Oxoford, UK, 2017; pp. 93–100. ISBN 9780128020999. [Google Scholar]
- Kabera, J.N.; Semana, E.; Mussa, A.R.; He, X. Plant secondary metabolites: Biosynthesis, classification, function and pharmacological properties. J. Pharm. Pharmacol. 2014, 2, 377–392. [Google Scholar]
- Guo, Z. The modification of natural products for medical use. Acta Pharm. Sin. B 2017, 7, 119–136. [Google Scholar] [CrossRef] [PubMed]
- Yao, H.; Liu, J.; Xu, S.; Zhu, Z.; Xu, J. The structural modification of natural products for novel drug discovery. Expert Opin. Drug Discov. 2017, 12, 121–140. [Google Scholar] [CrossRef] [PubMed]
- Evans, A.E.; Farber, S.; Brunet, S.; Mariano, P.J. Vincristine in the treatment of acute leukaemia in children. Cancer 1963, 16, 1302–1306. [Google Scholar] [CrossRef]
- Moore, A.; Pinkerton, R. Vincristine: Can its therapeutic index be enhanced? Pediatr. Blood Cancer 2009, 53, 1180–1187. [Google Scholar] [CrossRef] [PubMed]
- Almagro, L.; Fernández-Pérez, F.; Pedreño, M.A. Indole alkaloids from Catharanthus roseus: Bioproduction and their effect on human health. Molecules 2015, 20, 2973–3000. [Google Scholar] [CrossRef] [PubMed]
- Tang, K.; Pan, Q. Strategies for enhancing alkaloids yield in Catharanthus roseus via metabolic engineering approaches. In Catharanthus Roseus: Current Research and Future Prospects; Naeem, M., Aftab, T., Khan, M., Eds.; Springer International Publishing: Basel, Switzerland, 2017; pp. 1–16. [Google Scholar]
- Mu, F.; Yang, L.; Wang, W.; Luo, M.; Fu, Y.; Guo, X.; Zu, Y. Negative-pressure cavitation extraction of four main vinca alkaloids from Catharanthus roseus leaves. Molecules 2012, 17, 8742–8752. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Song, Y.; Su, Y.; Tian, Q.; Li, B.; Quan, J.; Deng, Y. Are PEGylated liposomes better than conventional liposomes? A special case for vincristine. Drug Deliv. 2016, 23, 1092–1100. [Google Scholar] [CrossRef] [PubMed]
- Sertel, S.; Fu, Y.; Zu, Y.; Rebacz, B.; Konkimalla, B.; Plinkert, P.K.; Krämer, A.; Gertsch, J.; Efferth, T. Molecular docking and pharmacogenomics of Vinca alkaloid and their monomeric precursor, vindoline and catharanthine. Biochem. Pharmacol. 2011, 81, 723–735. [Google Scholar] [CrossRef] [PubMed]
- Douer, D. Efficacy and safety of vincristine sulfate liposome injection in the treatment of adult acute lymphocytic leukaemia. Oncologist 2016, 21, 840–847. [Google Scholar] [CrossRef] [PubMed]
- Velde, M.E.; Kaspers, G.L.; Abbink, F.C.H.; Wilhelm, A.J.; Ket, J.C.F.; Berg, M.H. Vincristine-induced peripheral neuropathy in children with cancer: A systematic review. Crit. Rev. Oncol. Hematol. 2017, 114, 114–130. [Google Scholar] [CrossRef] [PubMed]
- Yoshihara, H.; Yoshimoto, Y.; Hosoya, Y.; Hasegawa, D.; Kawano, T.; Sakoda, A.; Okita, H.; Manabe, A. Infantile fibrosarcoma treated with postoperative vincristine and dactinomycin. Pediatr. Int. 2017, 59, 371–374. [Google Scholar] [CrossRef] [PubMed]
- Weaver, B.A. How Taxol/paclitaxel kills cancer cells. Mol. Biol. Cell 2014, 25, 2677–2681. [Google Scholar] [CrossRef] [PubMed]
- Bernabeu, E.; Cagel, M.; Lagomarsino, E.; Moretton, M.; Chiappetta, D.A. Paclitaxel: What has been done and the challenges remain ahead. Int. J. Pharm. 2017, 526, 474–495. [Google Scholar] [CrossRef] [PubMed]
- Bernabeu, E.; Gonzalez, L.; Cagel, M.; Gergic, E.P.; Moretton, M.A.; Chiappetta, D.A. Novel Soluplus1®-TPGS mixed micelles for encapsulation of paclitaxel with enhanced in vitro cytotoxicity on breast and ovarian cancer cell lines. Colloids Surf. B Biointerfaces 2016, 140, 403–411. [Google Scholar] [CrossRef] [PubMed]
- Howat, S.; Park, B.; Oh, I.S.; Jin, Y.W.; Lee, E.K.; Loake, G.J. Paclitaxel: Biosynthesis, production and future prospects. New Biotechnol. 2014, 31, 242–245. [Google Scholar] [CrossRef] [PubMed]
- Nicolaou, K.C.; Yang, Z.; Liu, J.J.; Ueno, H.; Nantermet, P.G.; Guy, R.K.; Claiborne, C.F.; Renaud, J.; Couladouros, E.A.; Paulvannan, K.; et al. Total synthesis of taxol. Nature 1994, 367, 630–634. [Google Scholar] [CrossRef] [PubMed]
- Fukaya, K.; Kodama, K.; Tanaka, Y.; Yamazaki, H.; Sugai, T.; Yamaguchi, Y.; Watanabe, A.; Oishi, T.; Sato, T.; Chida, N. Synthesis of Paclitaxel. 2. Construction of the ABCD ring and formal synthesis. Org. Lett. 2015, 17, 2574–2577. [Google Scholar] [CrossRef] [PubMed]
- Hirai, S.; Utsugi, M.; Iwamoto, M.; Nakada, M. Formal total synthesis of (−)-taxol through Pd-catalyzed eight-membered carbocyclic ring formation. Chemistry 2015, 21, 355–359. [Google Scholar] [CrossRef] [PubMed]
- Gallego, A.; Malik, S.; Yousefzadi, M.; Makhzoum, A.; Tremouillaux-Guiller, J.; Bonfill, M. Taxol from Corylus avellana: Paving the way for a new source of this anti-cancer drug. Plant Cell Tissue Organ Cult. 2017, 129, 1–16. [Google Scholar] [CrossRef]
- Li, B.-J.; Wang, H.; Gong, T.; Chen, J.-J.; Chen, T.-J.; Yang, J.-L.; Zhu, P. Improving 10-deacetylbaccatin III-10-β-O-acetyltransferase catalytic fitness for Taxol production. Nat. Commun. 2017, 8, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Baloglu, E.; Kingston, D.G.I. A new semisynthesis of paclitaxel from baccatin III. J. Nat. Prod. 1999, 62, 1068–1071. [Google Scholar] [CrossRef] [PubMed]
- Mandai, T.; Kuroda, A.; Okumoto, H.; Nakanishi, K.; Mikuni, K.; Hara, K.J.; Hara, K.Z. A semisynthesis of paclitaxel via a 10-deacetylbaccatin III derivative bearing a β-keto ester appendage. Tetrahedron Lett. 2000, 41, 243–246. [Google Scholar] [CrossRef]
- Liu, W.C.; Gonga, T.; Zhu, P. Advances in exploring alternative Taxol sources. RSC Adv. 2016, 6, 48800–48809. [Google Scholar] [CrossRef]
- Xiao, Z.; Morris-Natschke, S.L.; Lee, K.H. Strategies for the optimization of natural leads to anticancer drugs or drug candidates. Med. Res. Rev. 2016, 36, 32–91. [Google Scholar] [CrossRef] [PubMed]
- Wang, N.N.; Zhao, L.J.; Wu, L.N.; He, M.F.; Qu, J.W.; Zhao, Y.B.; Zhao, W.Z.; Li, J.S.; Wang, J.H. Mechanistic analysis of taxol-induced multidrug resistance in an ovarian cancer cell line. Asian Pac. J. Cancer Prev. 2013, 14, 4983–4988. [Google Scholar] [CrossRef] [PubMed]
- Barbuti, A.M.; Chen, Z.S. Paclitaxel through the ages of anticancer therapy: Exploring its role in chemoresistance and radiation therapy. Cancers 2015, 7, 2360–2371. [Google Scholar] [CrossRef] [PubMed]
- Nehate, C.; Jain, S.; Saneja, A.; Khare, V.; Alam, N.; Dubey, R.; Gupta, P.N. Paclitaxel formulations: Challenges and novel delivery options. Curr. Drug Deliv. 2014, 11, 666–686. [Google Scholar] [CrossRef] [PubMed]
- Soliman, H.H. nab-Paclitaxel as a potential partner with checkpoint inhibitors in solid tumors. Onco Targets Ther. 2017, 10, 101–112. [Google Scholar] [CrossRef] [PubMed]
- Zong, Y.; Wu, J.; Shen, K. Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: A systematic review and meta-analysis. Oncotarget 2017, 8, 17360–17372. [Google Scholar] [CrossRef] [PubMed]
- Xu, X.; Wang, L.; Xu, H.Q.; Huang, X.E.; Qian, Y.D.; Xiang, J. Clinical comparison between paclitaxel liposome (Lipusu®) and paclitaxel for treatment of patients with metastatic gastric cancer. Asian Pac. J. Cancer Prev. 2013, 14, 2591–2594. [Google Scholar] [CrossRef] [PubMed]
- Rivera, E.; Cianfrocca, M. Overview of neuropathy associated with taxanes for the treatment of metastatic breast cancer. Cancer Chemother. Pharmacol. 2015, 75, 659–670. [Google Scholar] [CrossRef] [PubMed]
- Wen, G.; Qu, X.X.; Wang, D.; Chen, X.X.; Tian, X.C.; Gao, F.; Zhou, X.L. Recent advances in design, synthesis and bioactivity of paclitaxel-mimics. Fitoterapia 2016, 110, 26–37. [Google Scholar] [CrossRef] [PubMed]
- Crown, J.; O’Leary, M.; Ooi, W.S. Docetaxel and paclitaxel in the treatment of breast cancer: A review of clinical experience. Oncologist 2004, 9, 24–32. [Google Scholar] [CrossRef] [PubMed]
- Vrignaud, P.; Semiond, D.; Benning, V.; Beys, E.; Bouchard, H.; Gupta, S. Preclinical profile of cabazitaxel. Drug Des. Dev. Ther. 2014, 8, 1851–1867. [Google Scholar] [CrossRef] [PubMed]
- De Morree, E.; van Soest, R.; Aghai, A.; de Ridder, C.; de Bruijn, P.; Ghobadi Moghaddam-Helmantel, I.; Burger, H.; Mathijssen, R.; Wiemer, E.; de Wit, R.; et al. Understanding taxanes in prostate cancer; importance of intratumoral drug accumulation. Prostate 2016, 76, 927–936. [Google Scholar] [CrossRef] [PubMed]
- Goyal, S.; Oak, E.; Luo, J.; Cashen, A.F.; Carson, K.; Fehniger, T.; DiPersio, J.; Bartlett, N.L.; Wagner-Johnston, N.D. Minimal activity of nanoparticle albumin-bound (nab) paclitaxel in relapsed or refractory lymphomas: Results of a phase-I study. Leuk. Lymphoma 2018, 59, 357–362. [Google Scholar] [CrossRef] [PubMed]
- Ricci, F.; Guffanti, F.; Damia, G.; Broggini, M. Combination of paclitaxel, bevacizumab and MEK162 in second line treatment in platinum-relapsing patient derived ovarian cancer xenografts. Mol. Cancer 2017, 16, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Gill, K.K.; Kamal, M.M.; Kaddoumi, A.; Nazzal, S. EGFR targeted delivery of paclitaxel and parthenolide co-loaded in PEG-Phospholipid micelles enhance cytotoxicity and cellular uptake in non-small cell lung cancer cells. J. Drug Deliv. Sci. Technol. 2016, 36, 150–155. [Google Scholar] [CrossRef]
- Ehrlich, A.; Booher, S.; Becerra, Y.; Borris, D.L.; Figg, W.D.; Turner, M.L.; Blauvelt, A. Micellar paclitaxel improves severe psoriasis in a prospective phase II pilot study. J. Am. Acad. Dermatol. 2004, 50, 533–540. [Google Scholar] [CrossRef] [PubMed]
- Dadgar, S.; Ramjan, Z.; Floriano, W.B. Paclitaxel is an inhibitor and its boron dipyrromethene derivative is a fluorescent recognition agent for botulinum neurotoxin subtype A. J. Med. Chem. 2013, 56, 2791–2803. [Google Scholar] [CrossRef] [PubMed]
- Kantarjian, H.M.; O’Brien, S.; Cortes, J. Homoharringtonine/omacetaxine mepesuccinate: The long and winding road to food and drug administration approval. Clin. Lymphoma Myeloma Leuk. 2013, 13, 530–533. [Google Scholar] [CrossRef] [PubMed]
- Butler, M.S.; Robertson, A.A.B.; Cooper, M.A. Natural product and natural product derived drugs in clinical trials. Nat. Prod. Rep. 2014, 31, 1612–1661. [Google Scholar] [CrossRef] [PubMed]
- Chang, Y.; Meng, F.-C.; Wang, R.; Wang, C.M.; Lu, X.-Y.; Zhang, Q.-W. Chemistry, bioactivity, and the structure-activity relationship of cephalotaxine-type alkaloids from Cephalotaxus sp. In Studies in Natural Products Chemistry Bioactive Natural Products; Atta-Ur-Rahman, F.R.S., Ed.; Elsevier Science Publishers: Amsterdam, The Netherlands, 2017; Volume 53, pp. 339–373. ISBN 978-0-444-63930-1. [Google Scholar]
- Lü, S.; Wang, J. Homoharringtonine and omacetaxine for myeloid hematological malignancies. J. Hematol. Oncol. 2014, 7, 1–10. [Google Scholar] [CrossRef] [PubMed]
- Gandhi, V.; Plunkett, W.; Cortes, J.E. Omacetaxine: A protein translation inhibitor for treatment of chronic myelogenous leucemia. Clin. Cancer Res. 2014, 20, 1735–1740. [Google Scholar] [CrossRef] [PubMed]
- Li, X.; Yin, X.; Wang, H.; Huang, J.; Yu, M.; Ma, Z.; Li, C.; Zhou, Y.; Yan, X.; Huang, S.; et al. The combination effect of homoharringtonine and ibrutinib on FLT3-ITD mutant acute myeloid leukaemia. Oncotarget 2017, 8, 12764–12774. [Google Scholar] [CrossRef] [PubMed]
- Chen, J.; Mu, Q.; Li, X.; Yin, X.; Yu, M.; Jin, J.; Li, C.; Zhou, Y.; Zhou, J.; Shanshan Suo, S.; et al. Homoharringtonine targets Smad3 and TGF-β pathway to inhibit the proliferation of acute myeloid leukaemia cells. Oncotarget 2017, 8, 40318–40326. [Google Scholar] [CrossRef] [PubMed]
- Pasic, I.; Lipton, J.H. Current approach to the treatment of chronic myeloid leukaemia. Leuk. Res. 2017, 55, 65–78. [Google Scholar] [CrossRef] [PubMed]
- Chung, C. Omacetaxine for treatment-resistant or treatment-intolerant adult chronic myeloid leukaemia. Am. J. Health Syst. Pharm. 2014, 71, 279–288. [Google Scholar] [CrossRef] [PubMed]
- Cortes, J.E.; Kantarjian, H.M.; Rea, D.; Wetzler, M.; Lipton, J.H.; Akard, L.; Khoury, H.J.; Michallet, M.; Guerci-Bresler, A.; Chuah, C.; et al. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukaemia: Results with 24 months of follow-up. Cancer 2015, 121, 1637–1644. [Google Scholar] [CrossRef] [PubMed]
- Damlaj, M.; Lipton, J.H.; Assouline, S.E. A safety evaluation of omacetaxine mepesuccinate for the treatment of chronic myeloid leukaemia. Expert Opin. Drug Saf. 2016, 15, 1279–1286. [Google Scholar] [CrossRef] [PubMed]
- Allan, E.K.; Holyoake, T.L.; Craig, A.R.; Jørgensen, H.G. Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells. Leukaemia 2011, 25, 985–994. [Google Scholar] [CrossRef] [PubMed]
- Lam, S.S.; Ho, E.S.; He, B.L.; Wong, W.W.; Cher, C.Y.; Ng, N.K.; Man, C.H.; Gill, H.; Cheung, A.M.; Ip, H.W.; et al. Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukaemia. Sci. Transl. Med. 2016, 8, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Heiblig, M.; Sobh, M.; Nicolini, F.E. Subcutaneous omacetaxine mepesuccinate in patients with chronic myeloid leukaemia in tyrosine kinase inhibitor-resistant patients: Review and perspectives. Leuk. Res. 2014, 38, 1145–1153. [Google Scholar] [CrossRef] [PubMed]
- Shen, A.Q.; Munteanu, M.; Khoury, H.J. Updated product label allows home administration of omacetaxine mepesuccinate. Oncologist 2014, 19, 1. [Google Scholar] [CrossRef] [PubMed]
- Akard, L.; Kantarjian, H.M.; Nicolini, F.E.; Wetzler, M.; Lipton, J.H.; Baccarani, M.; Jean Khoury, H.; Kurtin, S.; Li, E.; Munteanu, M.; et al. Incidence and management of myelosuppression in patients with chronic- and accelerated-phase chronic myeloid leukaemia treated with omacetaxine mepesuccinate. Leuk. Lymphoma 2016, 57, 654–665. [Google Scholar] [CrossRef] [PubMed]
- Saklani, A.; Kutty, S.K. Plant-derived compounds in clinical trials. Drug Discov. Today 2008, 13, 161–171. [Google Scholar] [CrossRef] [PubMed]
- Rizk, A.M.; Hammouda, F.M.; El-Missiry, M.M.; Radwan, H.M.; Evans, F.J. Biologically active diterpene esters from Euphorbia peplus. Phytochemistry 1985, 24, 1605–1606. [Google Scholar] [CrossRef]
- Ramsay, J.R.; Suhrbier, A.; Aylward, J.H.; Ogbourne, S.; Cozzi, S.J.; Poulsen, M.G.; Baumann, K.C.; Welburn, P.; Redlich, G.L.; Parsons, P.G. The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers. Br. J. Dermatol. 2011, 164, 633–636. [Google Scholar] [CrossRef] [PubMed]
- Ogbourne, S.M.; Parsons, P.G. The value of nature’s natural product library for the discovery of new chemical entities: The discovery of ingenol mebutate. Fitoterapia 2014, 98, 36–44. [Google Scholar] [CrossRef] [PubMed]
- Béres, T.; Dragull, K.; Pospíšil, J.; Tarkowská, D.; Dančák, M.; Bíba, O.; Tarkowski, P.; Doležal, K.; Strnad, M. Quantitative analysis of ingenol in Euphorbia species via validated isotope dilution ultra-high performance liquid chromatography tandem mass spectrometry. Phytochem. Anal. 2018, 29, 23–29. [Google Scholar] [CrossRef] [PubMed]
- Liang, X.; Grue-Sørensen, G.; Petersen, A.K.; Högberg, T. Semisynthesis of ingenol 3-angelate (PEP005): Efficient stereoconservative angeloylation of alcohols. Synlett 2012, 23, 2647–2652. [Google Scholar] [CrossRef]
- Liang, X.; Grue-Sørensen, G.; Månsson, K.; Vedsø, P.; Soor, A.; Stahlhut, M.; Bertelsen, M.; Engell, K.M.; Högberg, T. Syntheses, biological evaluation and SAR of ingenol mebutate analogues for treatment of actinic keratosis and non-melanoma skin cancer. Bioorg. Med. Chem. Lett. 2013, 23, 5624–5629. [Google Scholar] [CrossRef] [PubMed]
- Serova, M.; Ghoul, A.; Benhadji, K.A.; Faivre, S.; Le Tourneau, C.; Cvitkovic, E.; Lokiec, F.; Lord, J.; Ogbourne, S.M.; Calvo, F.; et al. Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. Mol. Cancer Ther. 2008, 7, 915–922. [Google Scholar] [CrossRef] [PubMed]
- Benhadji, K.A.; Serova, M.; Ghoul, A.; Cvitkovic, E.; Le Tourneau, C.; Ogbourne, S.M.; Lokiec, F.; Calvo, F.; Hammel, P.; Faivre, S.; et al. Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells. Br. J. Cancer 2008, 99, 1808–1815. [Google Scholar] [CrossRef] [PubMed]
- Collier, N.J.; Ali, F.R.; Lear, J.T. Ingenol mebutate: A novel treatment for actinic keratosis. Clin. Pract. 2014, 11, 295–306. [Google Scholar] [CrossRef]
- Rosen, R.H.; Gupta, A.K.; Tyring, S.K. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: Rapid lesion necrosis followed by lesion-specific immune response. J. Am. Acad. Dermatol. 2012, 66, 486–493. [Google Scholar] [CrossRef] [PubMed]
- Matias, D.; Bessa, C.; Simões, M.F.; Reis, C.P.; Saraiva, L.; Rijo, P. Natural products as lead protein kinase c modulators for cancer therapy. In Studies in Natural Products Chemistry Bioactive Natural Products; Atta-Ur-Rahman, F.R.S., Ed.; Elsevier Science Publishers: Amsterdam, The Netherlands, 2017; Volume 53, pp. 45–79. ISBN 978-0-444-63930-1. [Google Scholar]
- Kedei, N.; Lundberg, D.J.; Toth, A.; Welburn, P.; Garfield, S.H.; Blumberg, P.M. Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res. 2004, 64, 3243–3255. [Google Scholar] [CrossRef] [PubMed]
- Doan, H.Q.; Gulati, N.; Levis, W.R. Ingenol mebutate: Potential for further development of cancer immunotherapy. J. Drugs Dermatol. 2012, 11, 1156–1157. [Google Scholar] [PubMed]
- Tzogani, K.; Nagercoil, N.; Hemmings, R.J.; Samir, B.; Gardette, J.; Demolis, P.; Salmonson, T.; Pignatti, F. The European Medicines Agency approval of ingenol mebutate (Picato) for the cutaneous treatment of non-hyperkeratotic, non-hypertrophic actinic keratosis in adults: Summary of the scientific assessment of the Committee for Medicinal Products for Human Use (CHMP). Eur. J. Dermatol. 2014, 24, 457–463. [Google Scholar] [CrossRef] [PubMed]
- Kocaadam, B.; Şanlier, N. Curcumin, an active component of turmeric (Curcuma longa), and its effects on health. Crit. Rev. Food Sci. Nutr. 2017, 57, 2889–2895. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.J.; Pan, M.H.; Cheng, A.L.; Lin, L.I.; Ho, Y.S.; Hsieh, C.Y.; Lin, J.K. Stability of curcumin in buffer solutions and characterization of its degradation products. J. Pharm. Biomed. Anal. 1997, 15, 1867–1876. [Google Scholar] [CrossRef]
- Sinha, R.; Anderson, D.E.; McDonald, S.S.; Greenwald, P. Cancer risk and diet in India. J. Postgrad. Med. 2003, 49, 222–228. [Google Scholar] [PubMed]
- Perrone, D.; Ardito, F.; Giannatempo, G.; Dioguardi, M.; Troiano, G.; Lo Russo, L.; De Lillo, A.; Laino, L.; Lo Muzio, L. Biological and therapeutic activities and anticancer properties of curcumin. Exp. Ther. Med. 2015, 10, 1615–1623. [Google Scholar] [CrossRef] [PubMed]
- Pavan, A.R.; Silva, G.D.; Jornada, D.H.; Chiba, D.E.; Fernandes, G.F.; Man Chin, C.; Dos Santos, J.L. Unraveling the anticancer effect of curcumin and resveratrol. Nutrients 2016, 8, 628. [Google Scholar] [CrossRef] [PubMed]
- Imran, M.; Saeed, F.; Nadeem, M.; Arshad, U.M.; Ullah, A.; Suleria, H.A. Cucurmin, anticancer and antitumor perspectives—A comprehensive review. Crit. Rev. Food Sci. Nutr. 2016, 22, 1–23. [Google Scholar] [CrossRef] [PubMed]
- Redondo-Blanco, S.; Fernández, J.; Gutiérrez-del-Río, I.; Villar, C.J.; Lombó, F. New insights toward colorectal cancer chemotherapy using natural bioactive compounds. Front. Pharmacol. 2017, 8, 1–22. [Google Scholar] [CrossRef] [PubMed]
- Borges, G.Á.; Rêgo, D.F.; Assad, D.X.; Coletta, R.D.; De Luca Canto, G.; Guerra, E.N. In vivo and in vitro effects of curcumin on head and neck carcinoma: A systematic review. J. Oral Pathol. Med. 2017, 46, 3–20. [Google Scholar] [CrossRef] [PubMed]
- Sordillo, P.P.; Helson, L. Curcumin and cancer stem cells: Curcumin has asymmetrical effects on cancer and normal stem cells. Anticancer Res. 2015, 35, 599–614. [Google Scholar] [PubMed]
- Yu, H.J.; Ma, L.; Jiang, J.; Sun, S.Q. Protective effect of curcumin on neural myelin sheaths by attenuating interactions between the endoplasmic reticulum and mitochondria after compressed spinal cord. J. Spine 2016, 5, 1–6. [Google Scholar] [CrossRef]
- Di Martino, R.M.C.; Luppi, B.; Bisi, A.; Gobbi, S.; Rampa, A.; Abruzzo, A.; Bellutia, F. Recent progress on curcumin-based therapeutics: A patent review (2012–2016). Part I: Curcumin. Expert Opin. Ther. Pat. 2017, 27, 579–590. [Google Scholar] [CrossRef] [PubMed]
- Kumar, G.; Mittal, S.; Sak, K.; Tuli, H.S. Molecular mechanisms underlying chemopreventive potential of curcumin: Current challenges and future perspectives. Life Sci. 2016, 148, 313–328. [Google Scholar] [CrossRef] [PubMed]
- Kunnumakkara, A.B.; Bordoloi, D.; Harsha, C.; Banik, K.; Gupta, S.C.; Aggarwal, B.B. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways. Clin. Sci. 2017, 131, 1781–1799. [Google Scholar] [CrossRef] [PubMed]
- Schwertheim, S.; Wein, F.; Lennartz, K.; Worm, K.; Schmid, K.W.; Sheu-Grabellus, S.Y. Curcumin induces G2/M arrest, apoptosis, NF-κB inhibition, and expression of differentiation genes in thyroid carcinoma cells. J. Cancer Res. Clin. Oncol. 2017, 143, 1143–1154. [Google Scholar] [CrossRef] [PubMed]
- Yang, C.; Ma, X.; Wang, Z.; Zeng, X.; Hu, Z.; Ye, Z.; Shen, G. Curcumin induces apoptosis and protective autophagy in castration-resistant prostate cancer cells through iron chelation. Drug Des. Dev. Ther. 2017, 11, 431–439. [Google Scholar] [CrossRef] [PubMed]
- Dasiram, J.D.; Ganesan, R.; Kannan, J.; Kotteeswaran, V.; Sivalingam, N. Curcumin inhibits growth potential by G1 cell cycle arrest and induces apoptosis in p53-mutated COLO 320DM human colon adenocarcinoma cells. Biomed. Pharmacother. 2017, 86, 373–380. [Google Scholar] [CrossRef] [PubMed]
- Uwagawa, T.; Yanaga, K. Effect of NF-κB inhibition on chemoresistance in biliary–pancreatic cancer. Surg. Today 2015, 45, 1481–1488. [Google Scholar] [CrossRef] [PubMed]
- Fu, Z.; Chen, X.; Guan, S.; Yan, Y.; Lin, H.; Hua, Z.C. Curcumin inhibits angiogenesis and improves defective hematopoiesis induced by tumor-derived VEGF in tumor model through modulating VEGF-VEGFR2 signaling pathway. Oncotarget 2015, 6, 19469–19482. [Google Scholar] [CrossRef] [PubMed]
- Haris, P.; Mary, V.; Aparna, P.; Dileep, K.V.; Sudarsanakumar, C. A comprehensive approach to ascertain the binding mode of curcumin with DNA. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2017, 175, 155–163. [Google Scholar] [CrossRef] [PubMed]
- Ramya, P.V.; Angapelly, S.; Guntuku, L.; Singh Digwal, C.; Nagendra Babu, B.; Naidu, V.G.; Kamal, A. Synthesis and biological evaluation of curcumin inspired indole analogues as tubulin polymerization inhibitors. Eur. J. Med. Chem. 2017, 127, 100–114. [Google Scholar] [CrossRef] [PubMed]
- Gupta, S.C.; Patchva, S.; Aggarwal, B.B. Therapeutic roles of curcumin: Lessons learned from clinical trials. AAPS J. 2013, 15, 195–218. [Google Scholar] [CrossRef] [PubMed]
- Klippstein, R.; Bansal, S.S.; Al-Jamal, K.T. Doxorubicin enhances curcumin’s cytotoxicity in human prostate cancer cells in vitro by enhancing its cellular uptake. Int. J. Pharm. 2016, 514, 169–175. [Google Scholar] [CrossRef] [PubMed]
- Pimentel-Gutiérrez, H.J.; Bobadilla-Morales, L.; Barba-Barba, C.C.; Ortega-De-La-Torre, C.; Sánchez-Zubieta, F.A.; Corona-Rivera, J.R.; González-Quezada, B.A.; Armendáriz-Borunda, J.S.; Silva-Cruz, R.; Corona-Rivera, A. Curcumin potentiates the effect of chemotherapy against acute lymphoblastic leukaemia cells via downregulation of NF-κB. Oncol. Lett. 2016, 12, 4117–4124. [Google Scholar] [CrossRef] [PubMed]
- Rahimi, H.R.; Nedaeinia, R.; Shamloo, A.S.; Nikdoust, S.; Oskuee, R.K. Novel delivery system for natural products: Nano-curcumin formulations. Avicenna J. Phytomed. 2016, 6, 383–398. [Google Scholar] [PubMed]
- Liu, W.; Zhai, Y.; Heng, X.; Che, F.Y.; Chen, W.; Sun, D.; Zhai, G. Oral bioavailability of curcumin: Problems and advancements. J. Drug Target 2016, 24, 694–702. [Google Scholar] [CrossRef] [PubMed]
- Puneeth, H.R.; Ananda, H.; Kumar, K.S.S.; Rangappa, K.S.; Sharada, A.C. Synthesis and antiproliferative studies of curcumin pyrazole derivatives. Med. Chem. Res. 2016, 25, 1842–1851. [Google Scholar] [CrossRef]
- Ali-Seyed, M.; Jantan, I.; Vijayaraghavan, K.; Bukhari, S.N. Betulinic acid: Recent advances in chemical modifications, effective delivery, and molecular mechanisms of a promising anticancer therapy. Chem. Biol. Drug Des. 2016, 87, 517–536. [Google Scholar] [CrossRef] [PubMed]
- Pichette, A.; Liu, H.; Roy, C.; Tanguay, S.; Simard, F.; Lavoie, S. Selective oxidation of betulin for the preparation of betulinic acid, an antitumoral compound. Synth. Commun. 2004, 34, 3925–3937. [Google Scholar] [CrossRef]
- Holonec, L.; Ranga, F.; Crainic, D.; Truţa, A.; Socaciu, C. Evaluation of betulin and betulinic acid content in birch bark from different forestry areas of western carpathians. Not. Bot. Horti Agrobot. 2012, 40, 99–105. [Google Scholar] [CrossRef]
- Pisha, E.; Chai, H.; Lee, I.S.; Chagwedera, T.E.; Farnsworth, N.R.; Cordell, G.A.; Beecher, C.W.; Fong, H.H.; Kinghorn, A.D.; Brown, D.H. Discovery of betulinic acid a selective inhibitor of human-melanoma that functions by induction of apoptosis. Nat. Med. 1995, 10, 1046–1051. [Google Scholar] [CrossRef]
- Singh, S.; Sharma, B.; Kanwar, S.S.; Kumar, A. Lead phytochemicals for anticancer drug development. Front. Plant Sci. 2016, 7, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Lee, S.Y.; Kim, H.H.; Park, S.U. Recent studies on betulinic acid and its biological and pharmacological activity. EXCLI J. 2015, 14, 199–203. [Google Scholar] [CrossRef] [PubMed]
- Zhang, D.M.; Xu, H.G.; Wang, L.; Li, Y.J.; Sun, P.H.; Wu, X.M.; Wang, G.J.; Chen, W.M.; Ye, W.C. Betulinic acid and its derivatives as potential antitumor agents. Med. Res. Rev. 2015, 35, 1127–1155. [Google Scholar] [CrossRef] [PubMed]
- Gheorgheosu, D.; Duicu, O.; Dehelean, C.; Soica, C.; Muntean, D. Betulinic acid as a potent and complex antitumor phytochemical: A minireview. Anticancer Agents Med. Chem. 2014, 14, 936–945. [Google Scholar] [CrossRef] [PubMed]
- Ali, M.T.M.; Zahari, H.; Aliasak, A.; Lim, S.M.; Ramasamy, K.; Macabeoacabeo, A.P.G. Synthesis, characterization and cytotoxic activity of betulinic acid and sec-betulinic acid derivatives against human colorectal carcinoma. Orient. J. Chem. 2017, 33, 242–248. [Google Scholar] [CrossRef]
- Luo, R.; Fang, D.; Chu, P.; Wu, H.; Zhang, Z.; Tang, Z. Multiple molecular targets in breast cancer therapy by betulinic acid. Biomed. Pharmacother. 2016, 84, 1321–1330. [Google Scholar] [CrossRef] [PubMed]
- Shankar, E.; Zhang, A.; Franco, D.; Gupta, S. Betulinic acid-mediated apoptosis in human prostate cancer cells involves p53 and nuclear factor-kappa b (NF-κB) pathways. Molecules 2017, 22, 264. [Google Scholar] [CrossRef] [PubMed]
- Potze, L.; Di Franco, S.; Grandela, C.; Pras-Raves, M.L.; Picavet, D.I.; van Veen, H.A.; van Lenthe, H.; Mullauer, F.B.; van der Wel, N.N.; Luyf, A.; et al. Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification. Oncogene 2016, 35, 427–437. [Google Scholar] [CrossRef] [PubMed]
- Waechter, F.; Silva, G.S.; Willig, J.; de Oliveira, C.B.; Vieira, B.D.; Trivella, D.B.; Zimmer, A.R.; Buffon, A.; Pilger, D.A.; Gnoatto, S. Design, synthesis, and biological evaluation of betulinic acid derivatives as new antitumor agents for leukaemia. Anticancer Agents Med. Chem. 2017. [Google Scholar] [CrossRef] [PubMed]
- Jung, G.R.; Kim, K.J.; Choi, C.H.; Lee, T.B.; Han, S.I.; Han, H.K.; Lim, S.C. Effect of betulinic acid on anticancer drug-resistant colon cancer cells. Basic Clin. Pharmacol. Toxicol. 2007, 101, 277–285. [Google Scholar] [CrossRef] [PubMed]
- Gao, Y.; Jia, Z.L.; Kong, X.Y.; Li, Q.; Chang, D.Z.; Wei, D.Y.; Le, X.D.; Huang, S.D.; Huang, S.Y.; Wang, L.W.; Xie, K.P. Combining betulinic acid and mithramycin a effectively suppresses pancreatic cancer by inhibiting proliferation, invasion, and angiogenesis. Cancer Res. 2011, 71, 5182–5193. [Google Scholar] [CrossRef] [PubMed]
- Xu, Y.; Li, J.; Li, Q.J.; Feng, Y.L.; Pan, F. Betulinic acid promotes TRAIL function on liver cancer progression inhibition through p53/Caspase-3 signaling activation. Biomed. Pharmacother. 2017, 88, 349–358. [Google Scholar] [CrossRef] [PubMed]
- Yogeeswari, P.; Sriram, D. Betulinic acid and its derivatives: A review on their biological properties. Curr. Med. Chem. 2005, 12, 657–666. [Google Scholar] [CrossRef] [PubMed]
- Gismondi, A.; Reina, G.; Orlanducci, S.; Mizzoni, F.; Gay, S.; Terranova, M.L.; Canini, A. Nanodiamonds coupled with plant bioactive metabolites: A nanotech approach for cancer therapy. Biomaterials 2015, 38, 22–35. [Google Scholar] [CrossRef] [PubMed]
- Gismondi, A.; Nanni, V.; Reina, G.; Orlanducci, S.; Terranova, M.L.; Canini, A. Nanodiamonds coupled with 5,7-dimethoxycoumarin, a plant bioactive metabolite, interfere with the mitotic process in B16F10 cells altering the actin organization. Int. J. Nanomed. 2016, 11, 557–574. [Google Scholar] [CrossRef] [PubMed]
- Gupta, C.; Prakash, D.; Gupta, S. Cancer treatment with nano-diamonds. Front. Biosci. (Sch. Ed.) 2017, 9, 62–70. [Google Scholar] [CrossRef]
- Raj, R.; Mongia, P.; Sahu, S.K.; Ram, A. Nanocarriers based anticancer drugs: Current scenario and future perceptions. Curr. Drug Targets 2016, 17, 206–228. [Google Scholar] [CrossRef] [PubMed]
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Seca, A.M.L.; Pinto, D.C.G.A. Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application. Int. J. Mol. Sci. 2018, 19, 263. https://doi.org/10.3390/ijms19010263
Seca AML, Pinto DCGA. Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application. International Journal of Molecular Sciences. 2018; 19(1):263. https://doi.org/10.3390/ijms19010263
Chicago/Turabian StyleSeca, Ana M. L., and Diana C. G. A. Pinto. 2018. "Plant Secondary Metabolites as Anticancer Agents: Successes in Clinical Trials and Therapeutic Application" International Journal of Molecular Sciences 19, no. 1: 263. https://doi.org/10.3390/ijms19010263