Interference of cannabinoid agonists on the antitumor effect of oxaliplatin in murine colorectal adenocarcinoma tumors

Introduction: Oxaliplatin (OXL), an antineoplastic agent and first-line treatment for metastatic colorectal cancer, is primarily associated with neurotoxicity, manifested as dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid agonists have shown potential in preventing the development of PSN associated with OXL. However, to ensure therapeutic efficacy, it is necessary to investigate whether these agonists interfere with the antitumor effects of OXL.

Objective: To evaluate the impact of cannabinoid agonists on the antitumor efficacy of OXL in vivo and in vitro using murine colorectal adenocarcinoma (CT26) cells.

Methodology: Male Balb/c mice (CEUA No 16110422-0) were inoculated subcutaneously with CT26 cells and treated with WIN-55-212-2 (a non-selective cannabinoid agonist) and ACEA (a selective CB1 cannabinoid agonist), either alone or in combination with OXL. Tumor growth was assessed until day 12, and tumors were collected. PSN was evaluated using von Frey (VF) and acetone (TA) tests. CT26 cells were cultured in 96-well plates and treated with ascending concentrations of OXL, WIN, and ACEA. Synergism was assessed by combining OXL with ACEA and WIN. After 72 hours, cell viability was measured using the AlamarBlue assay.

Results: WIN and ACEA inhibited the development of PSN, reducing mechanical allodynia by 133% and 100%, respectively (p<0.05), in the VF test, and cold allodynia by 40% and 67% (p<0.05), in the TA test. Only the ACEA+OXL-treated groups showed antitumor effects (79%; p<0.05). WIN treatment did not alter the effect of OXL and had no effect alone. In vitro, OXL reduced cell viability with an IC50 of 2.23 μM. Both agonists decreased cell viability, with IC50 values of 7.09 μM (WIN) and 49.46 μM (ACEA). Additionally, the IC50 of OXL+WIN was reduced to 1.48 μM, suggesting a synergistic effect. The ACEA+OXL combination consistently showed an inhibition rate above 75% at all concentrations, indicating strong synergism.

Conclusion: WIN and ACEA exhibited antineuropathic effects in tumor-bearing animals. WIN reduced tumor cell growth in vitro but not in vivo, and in combination with OXL, enhanced its effect in vitro but not in vivo. ACEA alone did not show antitumor effects in vivo or in vitro, but when combined with OXL, it reduced tumor growth both in vitro and in vivo. These results are promising and suggest the need for further investigation into the use of cannabinoid agonists as adjuncts in colorectal cancer therapy with OXL.

Corresponding author: Paula Thaís Gomes Muniz (e-mail: paulathais2000@alu.ufc.br).