Anti-Cancer Activity of Cannabis sativa Phytocannabinoids: Molecular Mechanisms and Potential in the Fight against Ovarian Cancer and Stem Cells †
Abstract
:Simple Summary
Abstract
1. Introduction
2. Cannabis Compounds
3. The Endocannabinoid System and Cancer
4. Cannabinoid Receptors and Their Activation
5. Cannabinoids Anti-Cancer Activity
6. Concepts and Hallmarks of Cancer Stem Cells
7. Ovarian Cancer Stem Cells and Drug Resistance Mechanisms
8. Studies That Have Examined the Effectivity of Cannabis Compounds against OC
8.1. Preclinical
8.2. A Single Patient Case Study and Epidemiological Overview
9. Preclinical Evidence on the Cannabis Mode of Action on Genetic Pathways Related to OCSC
10. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Appendix A
References
- Cortez, A.J.; Tudrej, P.; Kujawa, K.A.; Lisowska, K.M. Advances in ovarian cancer therapy. Cancer Chemother. Pharmacol. 2018, 81, 17–38. [Google Scholar] [CrossRef]
- Ottevanger, P.B. Ovarian Cancer Stem Cells More Questions than Answers. In Seminars in Cancer Biology; Elsevier: Amsterdam, The Netherlands, 2017; pp. 67–71. [Google Scholar]
- Menon, U.; Gentry-Maharaj, A.; Burnell, M.; Singh, N.; Ryan, A.; Karpinskyj, C.; Carlino, G.; Taylor, J.; Massingham, S.K.; Raikou, M. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomised controlled trial. Lancet 2021, 397, 2182–2193. [Google Scholar] [CrossRef]
- Barnett, R. Ovarian cancer. Lancet 2016, 387, 1265. [Google Scholar] [CrossRef]
- Radu, M.R.; Prădatu, A.; Duică, F.; Micu, R.; Creţoiu, S.M.; Suciu, N.; Creţoiu, D.; Varlas, V.N.; Rădoi, V.E. Ovarian cancer: Biomarkers and targeted therapy. Biomedicines 2021, 9, 693. [Google Scholar] [CrossRef]
- Li, H.; Liu, Y.; Wang, Y.; Zhao, X.; Qi, X. Hormone therapy for ovarian cancer: Emphasis on mechanisms and applications. Oncol. Rep. 2021, 46, 223. [Google Scholar] [CrossRef] [PubMed]
- Corroon, J.; Sexton, M.; Bradley, R. Indications and administration practices amongst medical cannabis healthcare providers: A cross-sectional survey. BMC Fam. Pract. 2019, 20, 174. [Google Scholar] [CrossRef]
- Hanuš, L.O.; Meyer, S.M.; Muñoz, E.; Taglialatela-Scafati, O.; Appendino, G. Phytocannabinoids: A unified critical inventory. Nat. Prod. Rep. 2016, 33, 1357–1392. [Google Scholar] [CrossRef]
- Gülck, T.; Møller, B.L. Phytocannabinoids: Origins and biosynthesis. Trends Plant Sci. 2020, 25, 985–1004. [Google Scholar] [CrossRef]
- Aizpurua-Olaizola, O.; Soydaner, U.; Öztürk, E.; Schibano, D.; Simsir, Y.; Navarro, P.; Etxebarria, N.; Usobiaga, A. Evolution of the cannabinoid and terpene content during the growth of Cannabis sativa plants from different chemotypes. J. Nat. Prod. 2016, 79, 324–331. [Google Scholar] [CrossRef]
- Ramer, R.; Hinz, B. Cannabinoids as anticancer drugs. Adv. Pharmacol. 2017, 80, 397–436. [Google Scholar]
- Velasco, G.; Sánchez, C.; Guzmán, M. Towards the use of cannabinoids as antitumour agents. Nat. Rev. Cancer 2012, 12, 436–444. [Google Scholar] [CrossRef] [PubMed]
- McAllister, S.D.; Abood, M.E.; Califano, J.; Guzmán, M. Cannabinoid cancer biology and prevention. J. Natl. Cancer Inst. 2021, 2021, 99–106. [Google Scholar] [CrossRef]
- Bautista, J.L.; Yu, S.; Tian, L. Flavonoids in Cannabis sativa: Biosynthesis, bioactivities, and biotechnology. ACS Omega 2021, 6, 5119–5123. [Google Scholar] [CrossRef] [PubMed]
- Tahir, M.N.; Shahbazi, F.; Rondeau-Gagné, S.; Trant, J.F. The biosynthesis of the cannabinoids. J. Cannabis Res. 2021, 3, 7. [Google Scholar] [CrossRef]
- Di Marzo, V.; Piscitelli, F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics 2015, 12, 692–698. [Google Scholar] [CrossRef]
- Hillard, C.J. Circulating endocannabinoids: From whence do they come and where are they going? Neuropsychopharmacology 2018, 43, 155–172. [Google Scholar] [CrossRef] [PubMed]
- Laezza, C.; Pagano, C.; Navarra, G.; Pastorino, O.; Proto, M.C.; Fiore, D.; Piscopo, C.; Gazzerro, P.; Bifulco, M. The endocannabinoid system: A target for cancer treatment. Int. J. Mol. Sci. 2020, 21, 747. [Google Scholar] [CrossRef]
- Hinz, B.; Ramer, R. Anti-tumour actions of cannabinoids. Br. J. Pharmacol. 2019, 176, 1384–1394. [Google Scholar] [CrossRef]
- Kovalchuk, O.; Kovalchuk, I. Cannabinoids as anticancer therapeutic agents. Cell Cycle 2020, 19, 961–989. [Google Scholar] [CrossRef]
- Taylor, A.H.; Tortolani, D.; Ayakannu, T.; Konje, J.C.; Maccarrone, M. (Endo) cannabinoids and gynaecological cancers. Cancers 2020, 13, 37. [Google Scholar] [CrossRef]
- Fraguas-Sánchez, A.I.; Martín-Sabroso, C.; Torres-Suárez, A.I. Insights into the effects of the endocannabinoid system in cancer: A review. Br. J. Pharmacol. 2018, 175, 2566–2580. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abood, M.; Alexander, S.P.; Barth, F.; Bonner, T.I.; Bradshaw, H.; Cabral, G.; Casellas, P.; Cravatt, B.F.; Devane, W.A.; Di Marzo, V. Cannabinoid receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database. IUPHAR/BPS Guide Pharmacol. CITE 2019. [Google Scholar] [CrossRef]
- Maccarrone, M. Phytocannabinoids and endocannabinoids: Different in nature. Rend. Lincei. Sci. Fis. Nat. 2020, 31, 931–938. [Google Scholar] [CrossRef]
- Biringer, R.G. Endocannabinoid signaling pathways: Beyond CB1R and CB2R. J. Cell Commun. Signal 2021, 15, 335–360. [Google Scholar] [CrossRef] [PubMed]
- Duggan, P.J. The Chemistry of cannabis and cannabinoids. Aust. J. Chem. 2021, 74, 369–387. [Google Scholar] [CrossRef]
- Tomko, A.M.; Whynot, E.G.; Ellis, L.D.; Dupré, D.J. Anti-cancer potential of cannabinoids, terpenes, and flavonoids present in cannabis. Cancers 2020, 12, 1985. [Google Scholar] [CrossRef]
- Velasco, G.; Hernández-Tiedra, S.; Dávila, D.; Lorente, M. The use of cannabinoids as anticancer agents. Prog. Neuropsychopharmacol. Biol. Psychiatry 2016, 64, 259–266. [Google Scholar] [CrossRef]
- Blázquez, C.; Salazar, M.; Carracedo, A.; Lorente, M.; Egia, A.; González-Feria, L.; Haro, A.; Velasco, G.; Guzmán, M. Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression. Cancer Res. 2008, 68, 1945–1952. [Google Scholar] [CrossRef]
- Carracedo, A.; Lorente, M.; Egia, A.; Blázquez, C.; García, S.; Giroux, V.; Malicet, C.; Villuendas, R.; Gironella, M.; González-Feria, L. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell 2006, 9, 301–312. [Google Scholar] [CrossRef]
- Peeri, H.; Shalev, N.; Vinayaka, A.C.; Nizar, R.; Kazimirsky, G.; Namdar, D.; Anil, S.M.; Belausov, E.; Brodie, C.; Koltai, H. Specific Compositions of Cannabis sativa Compounds Have Cytotoxic Activity and Inhibit Motility and Colony Formation of Human Glioblastoma Cells In Vitro. Cancers 2021, 13, 1720. [Google Scholar] [CrossRef]
- Peeri, H.; Koltai, H. Cannabis biomolecule effects on cancer cells and cancer stem cells: Cytotoxic, anti-proliferative, and anti-migratory activities. Biomolecules 2022, 12, 491. [Google Scholar] [CrossRef] [PubMed]
- García-Morales, L.; Castillo, A.M.; Tapia Ramírez, J.; Zamudio-Meza, H.; Domínguez-Robles, M.d.C.; Meza, I. CBD reverts the mesenchymal invasive phenotype of breast cancer cells induced by the inflammatory cytokine IL-1β. Int. J. Mol. Sci. 2020, 21, 2429. [Google Scholar] [CrossRef]
- Jacobsson, S.O.; Rongård, E.; Stridh, M.; Tiger, G.; Fowler, C.J. Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability. Biochem. Pharmacol. 2000, 60, 1807–1813. [Google Scholar] [CrossRef]
- Ligresti, A.; Moriello, A.S.; Starowicz, K.; Matias, I.; Pisanti, S.; De Petrocellis, L.; Laezza, C.; Portella, G.; Bifulco, M.; Di Marzo, V. Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J. Pharmacol. Exp. Ther. 2006, 318, 1375–1387. [Google Scholar] [CrossRef] [PubMed]
- Anis, O.; Vinayaka, A.C.; Shalev, N.; Namdar, D.; Nadarajan, S.; Anil, S.M.; Cohen, O.; Belausov, E.; Ramon, J.; Mayzlish Gati, E. Cannabis-derived compounds cannabichromene and Δ9-tetrahydrocannabinol interact and exhibit cytotoxic activity against urothelial cell carcinoma correlated with inhibition of cell migration and cytoskeleton organization. Molecules 2021, 26, 465. [Google Scholar] [CrossRef] [PubMed]
- Brown, J.D. Potential adverse drug events with tetrahydrocannabinol (THC) due to drug–drug interactions. J. Clin. Med. 2020, 9, 919. [Google Scholar] [CrossRef]
- Alves, P.; Amaral, C.; Teixeira, N.; Correia-da-Silva, G. Cannabis sativa: Much more beyond Δ9-tetrahydrocannabinol. Pharmacol. Res. 2020, 157, 104822. [Google Scholar] [CrossRef]
- Jordan, C.T.; Guzman, M.L.; Noble, M. Cancer stem cells. N. Engl. J. Med. 2006, 355, 1253–1261. [Google Scholar] [CrossRef]
- Zhou, H.-M.; Zhang, J.-G.; Zhang, X.; Li, Q. Targeting cancer stem cells for reversing therapy resistance: Mechanism, signaling, and prospective agents. Signal Transduct. Target Ther. 2021, 6, 62. [Google Scholar] [CrossRef]
- Heft Neal, M.E.; Brenner, J.C.; Prince, M.E.P.; Chinn, S.B. Advancement in cancer stem cell biology and precision medicine-review article, head and neck cancer stem cell plasticity and the tumor microenvironment. Front. Cell Dev. Biol. 2022, 9, 660210. [Google Scholar] [CrossRef]
- Ayob, A.Z.; Ramasamy, T.S. Cancer stem cells as key drivers of tumour progression. J. Biomed. Sci. 2018, 25, 20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- He, L.; Wick, N.; Germans, S.K.; Peng, Y. The role of breast cancer stem cells in chemoresistance and metastasis in triple-negative breast cancer. Cancers 2021, 13, 6209. [Google Scholar] [CrossRef] [PubMed]
- Motohara, T.; Yoshida, G.J.; Katabuchi, H. The hallmarks of ovarian cancer stem cells and niches: Exploring their harmonious interplay in therapy resistance. Semin. Cancer Biol. 2021, 77, 182–193. [Google Scholar] [CrossRef] [PubMed]
- Zheng, X.; Yu, C.; Xu, M. Linking tumor microenvironment to plasticity of cancer stem cells: Mechanisms and application in cancer therapy. Front. Oncol. 2021, 11, 2552. [Google Scholar] [CrossRef]
- Qayoom, H.; Wani, N.A.; Alshehri, B.; Mir, M.A. An insight into the cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer. Future Oncol. 2021, 17, 4185–4206. [Google Scholar] [CrossRef]
- Keyvani, V.; Farshchian, M.; Esmaeili, S.-A.; Yari, H.; Moghbeli, M.; Nezhad, S.-R.K.; Abbaszadegan, M.R. Ovarian cancer stem cells and targeted therapy. J. Ovarian Res. 2019, 12, 1–11. [Google Scholar] [CrossRef]
- McAuliffe, S.M.; Morgan, S.L.; Wyant, G.A.; Tran, L.T.; Muto, K.W.; Chen, Y.S.; Chin, K.T.; Partridge, J.C.; Poole, B.B.; Cheng, K.-H. Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. Proc. Natl. Acad. Sci. USA 2012, 109, E2939–E2948. [Google Scholar] [CrossRef]
- Yang, W.; Yan, H.-X.; Chen, L.; Liu, Q.; He, Y.-Q.; Yu, L.-X.; Zhang, S.-H.; Huang, D.-D.; Tang, L.; Kong, X.-N. Wnt/β-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res. 2008, 68, 4287–4295. [Google Scholar] [CrossRef]
- Verras, M.; Papandreou, I.; Lim, A.L.; Denko, N.C. Tumor hypoxia blocks Wnt processing and secretion through the induction of endoplasmic reticulum stress. Mol. Cell. Biol. 2008, 28, 7212–7224. [Google Scholar] [CrossRef]
- Cao, S.; Tang, J.; Huang, Y.; Li, G.; Li, Z.; Cai, W.; Yuan, Y.; Liu, J.; Huang, X.; Zhang, H. The road of solid tumor survival: From drug-induced endoplasmic reticulum stress to drug resistance. Front. Mol. Biosci. 2021, 8, 620514. [Google Scholar] [CrossRef]
- Nami, B.; Donmez, H.; Kocak, N. Tunicamycin-induced endoplasmic reticulum stress reduces in vitro subpopulation and invasion of CD44+/CD24-phenotype breast cancer stem cells. Exp. Toxicol. Pathol. 2016, 68, 419–426. [Google Scholar] [CrossRef] [PubMed]
- Rodvold, J.J.; Chiu, K.T.; Hiramatsu, N.; Nussbacher, J.K.; Galimberti, V.; Mahadevan, N.R.; Willert, K.; Lin, J.H.; Zanetti, M. Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells. Sci. Signal. 2017, 10, eaah7177. [Google Scholar] [CrossRef] [PubMed]
- Tanabe, S.; Quader, S.; Cabral, H.; Ono, R. Interplay of EMT and CSC in cancer and the potential therapeutic strategies. Front. Pharmacol. 2020, 11, 904. [Google Scholar] [CrossRef] [PubMed]
- Loret, N.; Denys, H.; Tummers, P.; Berx, G. The role of epithelial-to-mesenchymal plasticity in ovarian cancer progression and therapy resistance. Cancers 2019, 11, 838. [Google Scholar] [CrossRef] [PubMed]
- Terry, S.; Chouaib, S. EMT in immuno-resistance. Oncoscience 2015, 2, 841. [Google Scholar] [CrossRef]
- Klemba, A.; Purzycka-Olewiecka, J.K.; Wcisło, G.; Czarnecka, A.M.; Lewicki, S.; Lesyng, B.; Szczylik, C.; Kieda, C. Surface markers of cancer stem-like cells of ovarian cancer and their clinical relevance. Contemp. Oncol./Współczesna Onkol. 2018, 2018, 48–55. [Google Scholar] [CrossRef]
- Bourguignon, L.Y. Matrix hyaluronan-CD44 interaction activates MicroRNA and LncRNA signaling associated with chemoresistance, invasion, and tumor progression. Front. Oncol. 2019, 9, 492. [Google Scholar] [CrossRef]
- Alvero, A.B.; Chen, R.; Fu, H.-H.; Montagna, M.; Schwartz, P.E.; Rutherford, T.; Silasi, D.-A.; Steffensen, K.D.; Waldstrom, M.; Visintin, I. Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle 2009, 8, 158–166. [Google Scholar] [CrossRef]
- Chau, W.; Ip, C.; Mak, A.; Lai, H.; Wong, A. c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/β-catenin–ATP-binding cassette G2 signaling. Oncogene 2013, 32, 2767–2781. [Google Scholar] [CrossRef]
- Nagaraj, A.B.; Joseph, P.; Kovalenko, O.; Singh, S.; Armstrong, A.; Redline, R.; Resnick, K.; Zanotti, K.; Waggoner, S.; DiFeo, A. Critical role of Wnt/β-catenin signaling in driving epithelial ovarian cancer platinum resistance. Oncotarget 2015, 6, 23720. [Google Scholar] [CrossRef]
- Hilton, J. Role of aldehyde dehydrogenase in cyclophosphamide-resistant L1210 leukemia. Cancer Res. 1984, 44, 5156–5160. [Google Scholar] [PubMed]
- Sun, Y.; Lai, X.; Yu, Y.; Li, J.; Cao, L.; Lin, W.; Huang, C.; Liao, J.; Chen, W.; Li, C. Inhibitor of DNA binding 1 (Id1) mediates stemness of colorectal cancer cells through the Id1-c-Myc-PLAC8 axis via the Wnt/β-catenin and Shh signaling pathways. Cancer Manag. Res. 2019, 11, 6855. [Google Scholar] [CrossRef]
- Lasorella, A.; Benezra, R.; Iavarone, A. The ID proteins: Master regulators of cancer stem cells and tumour aggressiveness. Nat. Rev. Cancer 2014, 14, 77–91. [Google Scholar] [CrossRef] [PubMed]
- Moldoveanu, T.; Czabotar, P.E. BAX, BAK, and BOK: A coming of age for the BCL-2 family effector proteins. Cold Spring Harb. Perspect. Biol. 2020, 12, a036319. [Google Scholar] [CrossRef] [PubMed]
- Fraguas-Sánchez, A.I.; Torres-Suárez, A.I.; Cohen, M.; Delie, F.; Bastida-Ruiz, D.; Yart, L.; Martin-Sabroso, C.; Fernández-Carballido, A. PLGA nanoparticles for the intraperitoneal administration of CBD in the treatment of ovarian cancer: In Vitro and In Ovo assessment. Pharmaceutics 2020, 12, 439. [Google Scholar] [CrossRef]
- Fraguas-Sánchez, A.; Fernández-Carballido, A.; Delie, F.; Cohen, M.; Martin-Sabroso, C.; Mezzanzanica, D.; Figini, M.; Satta, A.; Torres-Suárez, A. Enhancing ovarian cancer conventional chemotherapy through the combination with cannabidiol loaded microparticles. Eur. J. Pharm. Biopharm. 2020, 154, 246–258. [Google Scholar] [CrossRef]
- Barrie, A.M.; Gushue, A.C.; Eskander, R.N. Dramatic response to Laetrile and cannabidiol (CBD) oil in a patient with metastatic low grade serous ovarian carcinoma. Gynecol. Oncol. Rep. 2019, 29, 10. [Google Scholar] [CrossRef]
- Reece, A.S.; Hulse, G.K. Geotemporospatial and causal inferential epidemiological overview and survey of USA cannabis, cannabidiol and cannabinoid genotoxicity expressed in cancer incidence 2003–2017: Part 3–spatiotemporal, multivariable and causal inferential pathfinding and exploratory analyses of prostate and ovarian cancers. Arch. Public Health 2022, 80, 101. [Google Scholar]
- Nalli, Y.; Dar, M.S.; Bano, N.; Rasool, J.U.; Sarkar, A.R.; Banday, J.; Bhat, A.Q.; Rafia, B.; Vishwakarma, R.A.; Dar, M.J. Analyzing the role of cannabinoids as modulators of Wnt/β-catenin signaling pathway for their use in the management of neuropathic pain. Bioorg. Med. Chem. Lett. 2019, 29, 1043–1046. [Google Scholar] [CrossRef]
- Marselos, M.; Vasiliou, V.; Malamasi, M.; Alikaridis, F.; Kefalas, T. Effects of cannabis and tobacco on the enzymes of alcohol metabolism in the rat. Rev. Environ. Health 1991, 9, 31–38. [Google Scholar] [CrossRef]
- Greenhough, A.; Patsos, H.A.; Williams, A.C.; Paraskeva, C. The cannabinoid δ9-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Int. J. Cancer 2007, 121, 2172–2180. [Google Scholar] [CrossRef] [PubMed]
- Aviello, G.; Romano, B.; Borrelli, F.; Capasso, R.; Gallo, L.; Piscitelli, F.; Di Marzo, V.; Izzo, A.A. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J. Mol. Med. 2012, 90, 925–934. [Google Scholar] [CrossRef] [PubMed]
- Vallée, A.; Lecarpentier, Y.; Vallée, J.-N. Cannabidiol and the canonical WNT/β-catenin pathway in glaucoma. Int. J. Mol. Sci. 2021, 22, 3798. [Google Scholar] [CrossRef] [PubMed]
- Lo, H.-F.; Hong, M.; Szutorisz, H.; Hurd, Y.L.; Krauss, R.S. Δ9-tetrahydrocannabinol inhibits Hedgehog-dependent patterning during development. Development 2021, 148, dev199585. [Google Scholar] [CrossRef]
- Spiro, A.S.; Wong, A.; Boucher, A.A.; Arnold, J.C. Enhanced brain disposition and effects of Δ9-tetrahydrocannabinol in P-glycoprotein and breast cancer resistance protein knockout mice. PLoS ONE 2012, 7, e35937. [Google Scholar] [CrossRef]
- Etchart, M.G.; Anderson, L.L.; Ametovski, A.; Jones, P.M.; George, A.M.; Banister, S.D.; Arnold, J.C. In vitro evaluation of the interaction of the cannabis constituents cannabichromene and cannabichromenic acid with ABCG2 and ABCB1 transporters. Eur. J. Pharmacol. 2022, 922, 174836. [Google Scholar] [CrossRef]
- Brzozowska, N.; Li, K.M.; Wang, X.S.; Booth, J.; Stuart, J.; McGregor, I.S.; Arnold, J.C. ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice. PeerJ 2016, 4, e2081. [Google Scholar] [CrossRef]
- Libro, R.; Scionti, D.; Diomede, F.; Marchisio, M.; Grassi, G.; Pollastro, F.; Piattelli, A.; Bramanti, P.; Mazzon, E.; Trubiani, O. Cannabidiol modulates the immunophenotype and inhibits the activation of the inflammasome in human gingival mesenchymal stem cells. Front Physiol. 2016, 7, 559. [Google Scholar] [CrossRef]
- Misri, S.; Kaul, K.; Mishra, S.; Charan, M.; Verma, A.K.; Barr, M.P.; Ahirwar, D.K.; Ganju, R.K. Cannabidiol inhibits tumorigenesis in cisplatin-resistant non-small cell lung cancer via TRPV2. Cancers 2022, 14, 1181. [Google Scholar] [CrossRef]
- dos-Santos-Pereira, M.; Guimaraes, F.S.; Del-Bel, E.; Raisman-Vozari, R.; Michel, P.P. Cannabidiol prevents LPS-induced microglial inflammation by inhibiting ROS/NF-κB-dependent signaling and glucose consumption. Glia 2020, 68, 561–573. [Google Scholar] [CrossRef]
- Shrivastava, A.; Kuzontkoski, P.M.; Groopman, J.E.; Prasad, A. Cannabidiol induces programmed cell death in breast cancer cells by coordinating the cross-talk between apoptosis and autophagy. Mol. Cancer Ther. 2011, 10, 1161–1172. [Google Scholar] [CrossRef] [PubMed]
- Murase, R.; Kawamura, R.; Singer, E.; Pakdel, A.; Sarma, P.; Judkins, J.; Elwakeel, E.; Dayal, S.; Martinez-Martinez, E.; Amere, M. Targeting multiple cannabinoid anti-tumour pathways with a resorcinol derivative leads to inhibition of advanced stages of breast cancer. Br. J. Pharmacol. 2014, 171, 4464–4477. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Desprez, P.-Y.; Murase, R.; Limbad, C.; Woo, R.W.; Adrados, I.; Weitenthaler, K.; Soroceanu, L.; Salomonis, N.; McAllister, S.D. Cannabidiol treatment results in a common gene expression response across aggressive cancer cells from various origins. Cannabis Cannabinoid Res. 2021, 6, 148–155. [Google Scholar] [CrossRef] [PubMed]
- Bellio, C.; DiGloria, C.; Foster, R.; James, K.; Konstantinopoulos, P.A.; Growdon, W.B.; Rueda, B.R. PARP inhibition induces enrichment of DNA repair–proficient CD133 and CD117 positive ovarian cancer stem cells. Mol. Cancer Res. 2019, 17, 431–445. [Google Scholar] [CrossRef]
- Thakur, B.; Ray, P. Cisplatin triggers cancer stem cell enrichment in platinum-resistant cells through NF-κB-TNFα-PIK3CA loop. J. Exp. Clin. Cancer Res. 2017, 36, 164. [Google Scholar] [CrossRef]
- Namdar, D.; Anis, O.; Poulin, P.; Koltai, H. Chronological review and rational and future prospects of cannabis-based drug development. Molecules 2020, 25, 4821. [Google Scholar] [CrossRef]
- Mechoulam, R.; Ben-Shabat, S. From gan-zi-gun-nu to anandamide and 2-arachidonoylglycerol: The ongoing story of cannabis. Nat. Prod. Rep. 1999, 16, 131–143. [Google Scholar] [CrossRef]
- Russo, E.B. The case for the entourage effect and conventional breeding of clinical cannabis: No “strain,” no gain. Front. Plant Sci. 2019, 1969. [Google Scholar] [CrossRef]
- Guo, X.; Wang, X.-F. Signaling cross-talk between TGF-β/BMP and other pathways. Cell Res. 2009, 19, 71–88. [Google Scholar] [CrossRef]
Phytocannabinoid | Chemical Structure |
---|---|
THCA/THC | |
CBDA/CBD | |
CBGA/CBG | |
CBDVA/CBDV | |
CBCA/CBC |
Marker/Protein | Suggested Drug Resistance Mechanism(s) | References |
---|---|---|
CD44, a cell surface receptor, an integral membrane glycoprotein that binds several ECM components, including hyaluronan | Activation of NF-κB signaling pathway and the production of various cytokines | [44,58,59] |
CD117 (c-Kit), a type III tyrosine kinase receptor | Activation of PI3K/AKT and Wnt/β-catenin signaling pathway and increased expression of ABC transporters. | [44,47,60,61] |
ABC transporters | ABC transporters pump out of the cell various chemotherapies. | [44,47,60] |
ALDH, aldehyde dehydrogenase | Enhanced drug metabolism. | [44,47,61,62] |
CD133, a member of the pentaspan transmembrane protein family | Expression of ID1 proteins transcriptional regulators. | [44,57,63,64] |
Bcl-xL, BCL-2 protein family | Inhibition of the activation of the BAX and BAK pro-apoptotic proteins. | [47,65] |
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Koltai, H.; Shalev, N. Anti-Cancer Activity of Cannabis sativa Phytocannabinoids: Molecular Mechanisms and Potential in the Fight against Ovarian Cancer and Stem Cells. Cancers 2022, 14, 4299. https://doi.org/10.3390/cancers14174299
Koltai H, Shalev N. Anti-Cancer Activity of Cannabis sativa Phytocannabinoids: Molecular Mechanisms and Potential in the Fight against Ovarian Cancer and Stem Cells. Cancers. 2022; 14(17):4299. https://doi.org/10.3390/cancers14174299
Chicago/Turabian StyleKoltai, Hinanit, and Nurit Shalev. 2022. "Anti-Cancer Activity of Cannabis sativa Phytocannabinoids: Molecular Mechanisms and Potential in the Fight against Ovarian Cancer and Stem Cells" Cancers 14, no. 17: 4299. https://doi.org/10.3390/cancers14174299