Akt is upstream and MAPKs are downstream of NF-κB in paclitaxel-induced survival signaling events, which are down-regulated by curcumin contributing to their synergism

Abstract

Paclitaxel is the most promising chemotherapeutic agent of plant origin despite its high cost and dose-limiting toxicity. Our earlier report has shown that cervical cancer cells can be sensitized by curcumin to paclitaxel-induced apoptosis through down-regulation of NF-κB and Akt. In the present study we have attempted to decipher the signaling pathways regulating the synergism of paclitaxel and curcumin. The study has clearly proved that Akt and NF-κB function successively in the sequence of paclitaxel induced signaling events where Akt is upstream of NF-κB. While inhibition of NF-κB led to complete inhibition of the synergism of paclitaxel and curcumin, inhibition of Akt brought about only partial reduction of the same, suggesting that, apart from Akt, there are other pathways induced by paclitaxel leading to NF-κB activation, which are also down-regulated by curcumin. Inactivation of NF-κB did not affect the activation of Akt and survivin, while that of Akt significantly inhibited NF-κB and completely inhibited up-regulation of survivin. Up-regulation of Cyclin-D1, Cox-2, XIAP and cIAP1 and phosphorylation of MAPKs, were completely inhibited on inactivation of NF-κB assigning a key regulatory role to NF-κB in the synergestic effect of paclitaxel and curcumin. While up-regulation of survivin by paclitaxel is regulated by Akt, independent of NF-κB, inactivation of neither Akt nor NF-κB produced any change in Bcl-2 level suggesting a distinct pathway for its action. As curcumin could effectively down-regulate all these survival signals induced by paclitaxel, we suggest it as a potent chemosensitizer to improve the therapeutic index of paclitaxel.