Anti-Cancer Activity of Cannabis sativa Phytocannabinoids: Molecular Mechanisms and Potential in the Fight against Ovarian Cancer and Stem Cells

Abstract

Ovarian cancer (OC) is the most lethal gynecological malignancy, with about 70% of cases diagnosed only at an advanced stage. Cannabis sativa, which produces more than 150 phytocannabinoids, is used worldwide to alleviate numerous symptoms associated with various medical conditions. Recently, studies across a range of cancer types have demonstrated that the phytocannabinoids Δ9-trans-tetrahydrocannabinol (THC) and cannabidiol (CBD) have anti-cancer activity in vitro and in vivo, but also the potential to increase other drugs’ adverse effects. THC and CBD act via several different biological and signaling pathways, including receptor-dependent and receptor-independent pathways. However, very few studies have examined the effectiveness of cannabis compounds against OC. Moreover, little is known about the effectiveness of cannabis compounds against cancer stem cells (CSCs) in general and OC stem cells (OCSCs) in particular. CSCs have been implicated in tumor initiation, progression, and invasion, as well as tumor recurrence, metastasis, and drug resistance. Several hallmarks and concepts describe CSCs. OCSCs, too, are characterized by several markers and specific drug-resistance mechanisms. While there is no peer-reviewed information regarding the effect of cannabis and cannabis compounds on OCSC viability or development, cannabis compounds have been shown to affect genetic pathways and biological processes related to CSCs and OCSCs. Based on evidence from other cancer-type studies, the use of phytocannabinoid-based treatments to disrupt CSC homeostasis is suggested as a potential intervention to prevent chemotherapy resistance. The potential benefits of the combination of chemotherapy with phytocannabinoid treatment should be examined in ovarian cancer patients.

Genome-Scale Metabolic Reconstruction, Non-Targeted LC-QTOF-MS Based Metabolomics Data, and Evaluation of Anticancer Activity of Cannabis sativa Leaf Extracts

“…The obtained results confirmed the remarkable anticancer activity of the C. Sativa extracts against different carcinoma cell lines (AGS, A375 and A549). This agreed well with previous works that studied the anticancer activity of C. sativa on different cell lines such as melanoma [20], ovarian cancer [21], prostate cancer [22], and breast and pancreatic cancer [16], among others. The results are also in agreement with the biological activities based on both the chemotype and the extraction taken from the leaves of the plant.…”

“…It is established that C. sativa chemotypes’ rich cannabinoid and terpenoid content offer better pharmacological activities that are able to broaden clinical applications and improve therapeutic issues [ 17 , 18 , 19 ]. In the same way, remarkable anticancerogenic activity has been demonstrated for C. sativa extracts against different carcinoma cell lines such as melanoma [ 20 ], ovarian [ 21 ], prostate [ 22 ], breast [ 23 ], and pancreatic cancer [ 16 ]. These studies have revealed a reduction in tumor growth and promotion of apoptosis and autophagy in carcinoma cells [ 15 , 23 , 24 , 25 ].…”

Advances and Challenges in Cancer Stem Cells for Onco-Therapeutics

“…It is crucial that the accurate separation and recognition of malignant tissues be programed and designed, which entails understanding mechanisms that regulate the expansion of cancer stem cell colonies and the development of drug resistance in order to design effective tailored therapies. The immunomodulation, immune evasion, and impact resistance brought about by CSCs significantly alter the ability of the natural immune system to work in harmony [ 116 , 117 ]. In tumor progression, signaling via mTOR (mammalian target of rapamycin), SHH (sonic hedgehog), notch receptor, and Wnt/ β -catenin can be harnessed for modulating tumor progression [ 118 ].…”

Integrated transcriptome and cell phenotype analysis suggest involvement of PARP1 cleavage, Hippo/Wnt, TGF-β and MAPK signaling pathways in ovarian cancer cells response to cannabis and PARP1 inhibitor treatment

“…Phytocannabinoids have been found to affect cancer cells and tumors via several different genetic pathways and molecular mechanisms. For example, several signal transduction pathways can be activated by phytocannabinoids to induce cancer cell death, including cell cycle arrest, endoplasmic reticulum (ER) stress, oxidative stress, autophagy and/or apoptosis ( Hinz and Ramer, 2019 ; Kovalchuk and Kovalchuk, 2020 ; Tomko et al, 2020 ; Koltai and Shalev, 2022 ).…”