Efficacy of Cannabidiol Combination with Cisplatin or Paclitaxel against Platinum-Resistant Ovarian Cancer Cell Lines

Abstract

Cannabidiol (CBD) is one of the most abundant and commonly used cannabinoid of the Cannabis plant. Unlike tetrahydrocannabinol (THC), it lacks psychoactive properties, and thus it is considered to be a uniquely attractive cannabinoid for study. It has been used to treat various ailments, including epilepsy, anxiety, psychosis, inflammation, and cancer. Various in vitro, and to a lesser extent in vivo, studies have demonstrated the anti-cancer activity of CBD on different cancer cell types, and a few others showed that combining CBD with different chemotherapeutic agents exhibited variable interactions, ranging from antagonism, additive effect, and synergism. Few studies examined the anticancer activity of CBD, as well as its combination with cisplatin or paclitaxel, on ovarian cancer. Hence, the current study aimed to evaluate the anti-cancer activity of CBD, extracted from Lebanese Cannabis sativa plant, as monotherapy and in combination with conventional chemotherapeutic drugs cisplatin or paclitaxel on human ovarian adenocarcinoma OVCAR-3 and SK-OV-3 cell lines. CBD was extracted by Liquid Column Chromatography and confirmed by GC-MS. Cell survival was evaluated using the MTS cell proliferation assay. Monotherapy with CBD demonstrated a dose-dependent tumor growth inhibition at 72h, with the IC50 being 12.5 μg/ml for OVCAR-3 cell line and 12.3 μg/ml for SK-OV-3 cell line. The IC50 of cisplatin against OVCAR-3 and SK-OV-3 cell lines (1.1 and 3.3 μg/ml, respectively), and that of paclitaxel against SK-OV-3 cell line (9.9 μg/ml) were obtained as well. Additionally, applying the Chou-Talalay method using the CompuSyn software, the combination indexes (CI) were calculated to predict the interaction between CBD and the chemotherapeutic agents. The combination of CBD with either cisplatin or paclitaxel exhibited a significant antagonistic interaction against SK-OV-3 cell line when compared to individual treatment (CI > 1). However, at high cell growth inhibition rates (95% and 97%), mild synergism is detected (CI < 1) when combining CBD with cisplatin against this specific cell line. Thus, according to Drug Reduction Index (DRI), a combination of 6-fold less concentration of cisplatin with 1.3-fold less concentration of CBD yields a 95% cell growth inhibition. This synergistic interaction was confirmed in an in vitro experimentation setting. Pure antagonism was detected however when combining CBD and cisplatin against OVCAR-3 cell line. Evaluating the effect of CBD combined with paclitaxel against SK-OV-3 cell line demonstrated antagonism on all relevant inhibitory effect levels. Nonetheless, priming SK-OV-3 cells with CBD for 24h to sensitize them to the effect of cisplatin or paclitaxel treatment has shown to decrease the IC50 of the chemotherapeutic drugs. Similar results were revealed when the cells were primed with cisplatin or paclitaxel prior to be treated with CBD. The results suggest the potential benefit of sequential, rather than simultaneous, administration of CBD and chemotherapy to enhance therapy and overcome resistance. These findings, while demonstrating the potential benefit of CBD in treating ovarian cancer, call for additional caution when combining it with chemotherapeutic agents, specifically cisplatin and paclitaxel, as the effect is shown to be cell line and drug specific. Further studies are required for the validation of the results and better understanding of these interactions.