Anticancer properties of cannabidiol and Δ 9 -tetrahydrocannabinol and synergistic effects with gemcitabine and cisplatin in bladder cancer cell lines

With the legalization of cannabis in multiple jurisdictions throughout the world, a larger proportion of the population consumes cannabis. Several studies have demonstrated anti-tumor effects of components present in cannabis in different models. Unfortunately, little is known about the potential anti-tumoral effects of cannabinoids in bladder cancer and how cannabinoids could potentially synergize with chemotherapeutic agents. Our study aims to identify whether a combination of cannabinoids, like cannabidiol and Δ -tetrahydrocannabinol, with agents commonly used to treat bladder cancer, such as gemcitabine and cisplatin, can produce desirable synergistic effects. We also evaluated if co-treatment with different cannabinoids resulted in synergistic effects. We generated concentration curves with several drugs, including several cannabinoids, to identify the range at which they could exert anti-tumor effects in bladder cancer cell lines. We tested the cytotoxic effects of gemcitabine (up to 100 nM), cisplatin (up to 100 μM), and cannabinoids (up to 10 μM) in T24 and TCCSUP cells. We also evaluated the activation of the apoptotic cascade and whether cannabinoids have the ability to reduce invasion in T24 cells. Cannabidiol, Δ -tetrahydrocannabinol, cannabichromene, and cannabivarin reduce cell viability of bladder cancer cell lines, and their combination with gemcitabine or cisplatin may induce differential responses, from antagonistic to additive and synergistic effects, depending on the concentrations used. Cannabidiol and Δ -tetrahydrocannabinol were also shown to induce apoptosis via caspase-3 cleavage and reduce invasion in a Matrigel assay. Cannabidiol and Δ -tetrahydrocannabinol also display synergistic properties with other cannabinoids like cannabichromene or cannabivarin, although individual cannabinoids may be sufficient to reduce cell viability of bladder cancer cell lines. Our results indicate that cannabinoids can reduce human bladder transitional cell carcinoma cell viability, and that they can potentially exert synergistic effects when combined with other agents. Our in vitro results will form the basis for future studies in vivo and in clinical trials for the development of new therapies that could be beneficial for the treatment of bladder cancer in the future.