Abstract
INTRODUCTION: Cervical cancer remains a leading cause of cancer-related mortality among women globally, particularly in low- and middle-income countries. Cisplatin, a standard chemotherapeutic agent, is limited by severe toxicities and chemoresistance. This study aimed to assess the effects of cisplatin in combination with phytocannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on cell proliferation, morphology, cell cycle progression, cell death, and DNA damage. METHODS: Synergistic interactions between THC, CBD, and cisplatin were assessed in HeLa, SiHa, and MCF-12A cells using the checkerboard assay and SRB assay. Cell morphology, cell cycle progression, apoptosis induction, autophagic activity, and DNA repair gene expression were evaluated using various techniques. RESULTS: The THC-CBD-cisplatin combination exhibited the strongest apoptotic response in cancer cells (HeLa 53%, SiHa 58%), while minimally affecting MCF-12A cells (32%). Cannabinoid co-treatment amplified the antiproliferative and pro-apoptotic effects of cisplatin in HeLa and SiHa cells. The triple combination induced a G2/M arrest in HeLa cells and sub-G1 accumulation in SiHa cells. Autophagic activity, indicated by LC3B puncta formation, increased in HeLa and SiHa cells following THC and CBD exposure. DNA repair genes XRCC1 and RAD51 were downregulated by the cannabinoid-cisplatin combination. CONCLUSION: These findings demonstrate that combining THC and CBD with cisplatin results in enhanced and mechanistically diverse anticancer effects, with a higher degree of selectivity for cervical cancer cells compared to non-cancerous MCF-12A cells by inducing apoptosis and autophagy while inhibiting DNA repair capacity. This study highlights the potential of cannabinoid-based combination therapies as a promising approach for cervical cancer treatment.