Synergistic cytotoxicity of curcumin and plumbagin via reactive oxygen species mediated-apoptosis and cell cycle arrest in cervical cancer cell line

Abstract

Cervical cancer is the fourth most frequently diagnosed cancer in women worldwide. This study explored the synergistic anticancer effects of curcumin (Cur) and plumbagin (PL) in a human cervical cancer cell line (HeLa). A concentration-dependent decline in cell viability was recorded in response to curcumin and plumbagin singlet treatment with the IC₅₀ value of 7.8 μM and 6 μM, respectively. However, the combination of Cur + PL showed significantly enhanced cytotoxicity compared with the singlet compounds. Moreover, normal human lung fibroblast cell (PCS-201-013) did not exhibit significant cytotoxicity up to the IC₅₀ values of these compounds. The combined treatment led to cell cycle arrest at the G₂/M phase and 40 % induction of apoptosis compared to untreated/solvent controls. The co-treatment (Cur + PL) also demonstrated an increased expression of pro-apoptotic (Bax) and tumor suppression (p53) genes, along with the reduced expression of the anti-apoptotic gene (Bcl-2). Moreover, the application of plumbagin, curcumin, or combination of both resulted in a notable enhancement of reactive oxygen species (ROS) generation and depolarization of mitochondrial membrane potential (MMP) when compared to the untreated control. These results demonstrated the possible synergistic effect of Cur + PL combination and highlighted their significantly enhanced therapeutic potential, which could be further exploited as a possible candidate for cervical cancer treatment. However, further validation is required in a suitable xenograft model so that this potent combination could be exploited in clinics.