The Molecular Anti-metastatic Potential of CBD and THC from Lebanese Cannabis Via Apoptosis Induction and Alterations in Autophagy

Overview

Journal Sci Rep

Specialty Science

Date 2024 Oct 28

PMID 39463375

Authors

Maria Younes

Marissa El Hage

Wassim Shebaby

Sahar Al Toufaily

Jana Ismail

Hassan Y Naim

Mohammad Mroueh

Sandra Rizk

Affiliations

Soon will be listed here.

Abstract

The medicinal plant Cannabis sativa L. (C. sativa) is currently being extensively studied to determine the full extent of its therapeutic pharmacological potential. Δ-tetrahydocannabinol (THC) and cannabidiol (CBD) are the most thoroughly investigated compounds. We aimed to explore the anticancer activity of cannabinoids mixture isolated from the Lebanese C. sativa plant in ratios comparable to the local medicinal plant, to elucidate its mechanism of action in breast cancer cells in vitro. Cells were subjected to cytotoxicity assay, cell cycle analysis, Annexin V/PI dual staining, cell death ELISA, immunofluorescence, in addition to western blot analysis of apoptotic and autophagy markers. We further evaluated the anti-metastatic effect of cannabinoids on MDA-MB-231 using the scratch wound-healing, trans-well migration and invasion assays. Our results revealed the promising therapeutic benefits of CBD/THC on inhibiting the growth of breast cancer cells by promoting cellular fragmentation, phosphatidylserine translocation to the outer membrane leaflet and DNA fragmentation in both cell lines while inhibiting the motility of the triple negative breast cancer cells. In our study, CBD/THC mixture was found to exhibit a pro-apoptotic activity via the activation of the mitochondrial apoptotic pathway, independent from ROS production while also suggesting the activation of a caspase-dependent apoptotic pathway. Even though autophagy was altered upon exposure to the cannabinoid mixture, our data suggested that it is not the mechanism responsible of inducing cell death. In conclusion, our study demonstrates the promising therapeutic benefits of CBD and THC isolated from the Lebanese C. sativa plant on breast cancer cells in vitro.

References

Cho D, Jo Y, Hwang J, Lee Y, Roh S, Kim J . Caspase-mediated cleavage of ATG6/Beclin-1 links apoptosis to autophagy in HeLa cells. Cancer Lett. 2008; 274(1):95-100. DOI: 10.1016/j.canlet.2008.09.004. View

Velasco G, Hernandez-Tiedra S, Davila D, Lorente M . Corrigendum to "The use of cannabinoids as anticancer agents" [Prog. Neuro-Psychopharmacol. Biol. Psychiatry 64 (2016) 259-266]. Prog Neuropsychopharmacol Biol Psychiatry. 2017; 74:57. DOI: 10.1016/j.pnpbp.2016.12.005. View

de Brito Siqueira A, Cremasco P, Bahu J, Pioli da Silva A, Melo de Andrade L, Gonzalez P . Phytocannabinoids: Pharmacological effects, biomedical applications, and worldwide prospection. J Tradit Complement Med. 2023; 13(6):575-587. PMC: 10658372. DOI: 10.1016/j.jtcme.2023.08.006. View

Lombard C, Nagarkatti M, Nagarkatti P . Targeting cannabinoid receptors to treat leukemia: role of cross-talk between extrinsic and intrinsic pathways in Delta9-tetrahydrocannabinol (THC)-induced apoptosis of Jurkat cells. Leuk Res. 2005; 29(8):915-22. DOI: 10.1016/j.leukres.2005.01.014. View

Atalay S, Jarocka-Karpowicz I, Skrzydlewska E . Antioxidative and Anti-Inflammatory Properties of Cannabidiol. Antioxidants (Basel). 2019; 9(1). PMC: 7023045. DOI: 10.3390/antiox9010021. View

Massi P, Vaccani A, Ceruti S, Colombo A, Abbracchio M, Parolaro D . Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J Pharmacol Exp Ther. 2003; 308(3):838-45. DOI: 10.1124/jpet.103.061002. View

Shebaby W, Saliba J, Faour W, Ismail J, Hage M, Daher C . In vivo and in vitro anti-inflammatory activity evaluation of Lebanese Cannabis sativa L. ssp. indica (Lam.). J Ethnopharmacol. 2020; 270:113743. DOI: 10.1016/j.jep.2020.113743. View

Niloy N, Hediyal T, Vichitra C, Sonali S, Chidambaram S, Gorantla V . Effect of Cannabis on Memory Consolidation, Learning and Retrieval and Its Current Legal Status in India: A Review. Biomolecules. 2023; 13(1). PMC: 9855787. DOI: 10.3390/biom13010162. View

Volkmann N, Marassi F, Newmeyer D, Hanein D . The rheostat in the membrane: BCL-2 family proteins and apoptosis. Cell Death Differ. 2013; 21(2):206-15. PMC: 3890954. DOI: 10.1038/cdd.2013.153. View

10.

Peeri H, Koltai H . Cannabis Biomolecule Effects on Cancer Cells and Cancer Stem Cells: Cytotoxic, Anti-Proliferative, and Anti-Migratory Activities. Biomolecules. 2022; 12(4). PMC: 9028333. DOI: 10.3390/biom12040491. View

11.

Mashabela M, Kappo A . Anti-Cancer and Anti-Proliferative Potential of Cannabidiol: A Cellular and Molecular Perspective. Int J Mol Sci. 2024; 25(11). PMC: 11171526. DOI: 10.3390/ijms25115659. View

12.

Hall W, Stjepanovic D, Caulkins J, Lynskey M, Leung J, Campbell G . Public health implications of legalising the production and sale of cannabis for medicinal and recreational use. Lancet. 2019; 394(10208):1580-1590. DOI: 10.1016/S0140-6736(19)31789-1. View

13.

McAllister S, Chan C, Taft R, Luu T, Abood M, Moore D . Cannabinoids selectively inhibit proliferation and induce death of cultured human glioblastoma multiforme cells. J Neurooncol. 2005; 74(1):31-40. DOI: 10.1007/s11060-004-5950-2. View

14.

Cardiff R, Borowsky A . At last: classification of human mammary cells elucidates breast cancer origins. J Clin Invest. 2014; 124(2):478-80. PMC: 3904633. DOI: 10.1172/JCI73910. View

15.

Takeda S, Yoshida K, Nishimura H, Harada M, Okajima S, Miyoshi H . Δ(9)-Tetrahydrocannabinol disrupts estrogen-signaling through up-regulation of estrogen receptor β (ERβ). Chem Res Toxicol. 2013; 26(7):1073-9. PMC: 4018723. DOI: 10.1021/tx4000446. View

16.

Khodapasand E, Jafarzadeh N, Farrokhi F, Kamalidehghan B, Houshmand M . Is Bax/Bcl-2 ratio considered as a prognostic marker with age and tumor location in colorectal cancer?. Iran Biomed J. 2015; 19(2):69-75. PMC: 4412916. DOI: 10.6091/ibj.1366.2015. View

17.

Daris B, Tancer Verboten M, Knez Z, Ferk P . Cannabinoids in cancer treatment: Therapeutic potential and legislation. Bosn J Basic Med Sci. 2018; 19(1):14-23. PMC: 6387667. DOI: 10.17305/bjbms.2018.3532. View

18.

Cherkasova V, Wang B, Gerasymchuk M, Fiselier A, Kovalchuk O, Kovalchuk I . Use of Cannabis and Cannabinoids for Treatment of Cancer. Cancers (Basel). 2022; 14(20). PMC: 9600568. DOI: 10.3390/cancers14205142. View

19.

OReilly E, Khalifa K, Cosgrave J, Azam H, Prencipe M, Simpson J . Cannabidiol Inhibits the Proliferation and Invasiveness of Prostate Cancer Cells. J Nat Prod. 2023; 86(9):2151-2161. PMC: 10521019. DOI: 10.1021/acs.jnatprod.3c00363. View

20.

Blebea N, Hancu G, Vlad R, Pricopie A . Applications of Capillary Electrophoresis for the Determination of Cannabinoids in Different Matrices. Molecules. 2023; 28(2). PMC: 9862621. DOI: 10.3390/molecules28020638. View