Evaluation of the effects of cannabinoids CBD and CBG on human ovarian cancerc ells in vitro

Introduction:

Ovarian cancer, with over a 90% reoccurrence within 18 months of treatment, and approximately a 30% mortality rate after 5 years, is the leading cause of death in cases of gynaecological malignancies. Acquired resistance, and toxic side effects by clinically used agents are major challenges associated with current treatments, indicating the need for new approaches in ovarian cancer treatment. Increased tumour cell proliferation associated with upregulation of cannabinoid (CB) receptors has been observed in ovarian cancer. As cannabinoids reported to bind to CB receptors, and can potentially modulate their downstream signalling, this raises the possibility of cannabinoids as potential anticancer drugs for ovarian cancer treatment. Amongst the cannabinoids, non-psychoactive CBD and CBG have been shown to have anticancer activities towards prostate and colon cancer cells through multiple mechanisms of action. However, CBD and CBG have yet to be investigated in relation to ovarian cancer therapy either in vitro or in vivo.

Aim:

The aims of this study were to evaluate the potential cytotoxic effects of CBD and CBG in human ovarian cancer cells, their ability to potentiate existing clinically used agents for ovarian cancer, and to perform initial mode of action studies in vitro.

Methods:

In this study, the cytotoxic effects of CBD and CBG were evaluated in several ovarian cancer cell lines, and in non-cancer cells. Chemosensitivity assays were performed to determine the relative potency, selectivity and combination effects of the cannabinoids CBD and CBG. Effects on the cell cycle, cell death by apoptosis and ROS levels in ovarian cancer cells when treated with CBD or CBG were evaluated. The expression of the cannabinoid receptors CB1, CB2 and GPR55 in ovarian cancer cells, and their possible contribution to CBD and CBG cytotoxicity was also assessed.

Results:

CBD and CBG induced dose-dependent and time-dependent cytotoxic effects on the ovarian cancer cells tested with activity at micromolar concentrations towards the A2780 and A2780/CP70 cancer cells whilst displaying less activity against the non-cancer cells. CBD was the more potent of the two cannabinoids. However, the difference observed was not significant compared to CBG. CBD and CBG in combination with the established chemotherapeutic drug carboplatin showed synergistic effects in the cancer cells but importantly, CBD and CBG did not synergise with carboplatin in the non-cancer ARPE19 cells. Preliminary data suggested that the cytotoxicity of CBD and CBG is dependent, in part at least, on the cannabinoid receptor GPR55 whilst CB2 cannabinoid receptor status did not affect the cytotoxicity of the cannabinoids in ovarian cancer cells. GPR55 expression analysis in ovarian cancer tissues showed that the target is expressed at the mRNA level in ovarian cancer patient samples.

Conclusions:

Both CBD and CBG showed preferential cytotoxicity against the ovarian cancer cells analysed compared to the non-cancer cells; however, this was less than for carboplatin. Importantly, in contrast to carboplatin, CBD and CBG showed similar activity towards cisplatin sensitive and cisplatin resistant cells indicating distinctive mechanisms of action to platinum drugs. Preferential cytotoxicity towards cancer cells in vitro and ability to potentiate carboplatin and overcome cisplatin resistance identify CBD and CBG as promising candidates that warrant further investigation, both in terms of detailed mechanism of action studies and also in vivo studies to assess whether this promising activity translates into an in vivo setting and their potential for further progression towards the clinic.