Paclitaxel (
Taxol) is currently used as the front-line chemotherapeutic agent for several
cancers including ovarian
carcinoma; however, the
drug frequently induces drug resistance through multiple mechanisms. The new strategy of using natural compounds in combination
therapies is highly attractive because those compounds may enhance the efficacy of
chemotherapy. In this study, we found that
tectorigenin, an isoflavonoid isolated from flower of Pueraria thunbergiana, enhanced the growth-inhibitory effect of
paclitaxel in
paclitaxel-resistant
ovarian cancer cells (MPSC1(TR), A2780(TR) and SKOV3(TR)) as well as their naive counterparts. The combination of
tectorigenin with
paclitaxel resulted in a synergistic apoptosis compared with either agent alone through activation of caspases-3, -8 and -9. Treatment with
tectorigenin inhibited the nuclear translocation of NFκB and the expression of NFκB-dependent genes such as FLIP, XIAP, Bcl-2, Bcl-xL and COX-2, which are known to be associated with chemoresistance. In addition, the
tectorigenin-
paclitaxel combination inhibited the phosphorylation of IκB and IKK and the activation of Akt in
paclitaxel-resistant
cancer cells. Moreover,
tectorigenin-
paclitaxel-induced cell growth inhibition was enhanced by pretreatment with the Akt inhibitor
LY294002 or overexpression of the dominant negative Akt (Akt-DN), but reduced by overexpression of constitutively activated Akt (Akt-Myr). Furthermore, we found that Akt-Myr, at least in part, reversed
tectorigenin-
paclitaxel-induced nuclear translocation of NFκB and the phosphorylation of IκB and IKK. These data suggest that
tectorigenin could sensitize
paclitaxel-resistant human
ovarian cancer cells through inactivation of the Akt/IKK/IκB/NFκB signaling pathway, and promise a new intervention to chemosensitize
paclitaxel-induced cytotoxicity in
ovarian cancer.