Tea polyphenols enhance cisplatin chemosensitivity in cervical cancer cells via induction of apoptosis

Aim: Constitutive activation of nuclear factor-kappaB (NF-kappa B) and Akt has been implicated in chemoresistance as well as inhibition of apoptosis to cisplatin (CDDP), therefore, we examined whether (-) epigallocateocatechin-3-gallate (EGCG) or theaflavins (TF) could sensitize human cancer cells to CDDP via induction of apoptosis mediated by the inactivation of NF-kappa B and Akt signaling. Main methods: Human cervical cancer cells (HeLa and SiHa cells) were treated with EGCG or TF and CDDP alone and with their combinations, further their effects on cell viability were evaluated. Western blotting was used for examining the apoptotic signaling proteins and inhibition of NF-kappa B activation. Levels of reactive oxygen species (ROS) production and mitochondria membrane potential (Delta Psi m) were examined by flow cytometry. Key findings: The combined treatment of EGCG or TF with CDDP elicited significant inhibition of cell growth in comparison to either of them in both cell lines (p <0.05). Combinatorial treatment of both compounds potentially induced apoptosis by inhibiting the activation of Akt and NF-kappa B through blocking phosphotylation of inhibitor kappa B alpha. These combinations acted in concert to induce increase in ROS level, release of cytochrome-c and expression of p53 and Bax, with decrease in cellular glutathione contents, Delta Psi m, and Bcl-2 expression, thereby eventually resulting in the activation of caspases, poly(ADP)ribose polymerase cleavage and apoptosis of cancer cells. Significance: Study suggests that both EGCG and TF chemosensitize the cervical cancer cells to CDDP-induced growth inhibition and apoptosis. By these combinations similar to 4 folds increase in CDDP induced-apoptosis with dose advantage of similar to 3 times could be achieved. (C) 2013 Elsevier Inc. All rights reserved.