Tectorigenin sensitizes paclitaxel-resistant human ovarian cancer cells through downregulation of the Akt and NFκB pathway

Abstract

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.

Hsp90 inhibitor SY-016 induces G2/M arrest and apoptosis in paclitaxel-resistant human ovarian cancer cells

“…NF-κB has been recognized as one of the most important targets of the Akt signaling pathway. The activation of NF-κB is dependent on the phosphorylation of IκB under the control of the Akt kinase (16). Simultaneous activation of multiple signaling pathways contributes to a survival advantage …”

“…Furthermore, the Akt/NF-κB signaling pathway serves a key role in regulating cell growth, survival and chemoresistance in ovarian and gastric cancer cells (17,18). Akt and NF-κB are involved in ovarian cancer chemoresistance through the upregulation of FLICE-inhibitory protein, XIAP, Bcl-2 and survivin (16). Similarly, reduced malignant potential was observed when NF-κB was blocked in ovarian cancer cells (19).…”

ABCG2 gene amplification and expression in esophageal cancer cells with acquired adriamycin resistance

“…A tolerance to one agent is often accompanied by cross-resistance to a variety of other compounds. This MDR is caused by several mechanisms, including increased drug efflux (1)(2)(3)(4)(5)(6)(7)(8), enhanced drug detoxification, alterations of targets, and modification of DNA damage repair systems (9)(10)(11) and apoptosis pathways (12). The drug efflux effect is mediated by the enhanced expression of one or more ATP-binding cassette (ABC) transporters (2,(13)(14)(15).…”

Tectorigenin ablates the inflammation-induced epithelial–mesenchymal transition in a co-culture model of human lung carcinoma

“…During EMT cancer cells acquire 30 fibroblast-like properties, thus losing their defined cell -cell and cell-31 extracellular matrix contacts [4]. At the molecular level EMT is 32 characterized by down regulation of E-cadherin and cytokeratins, the 33 process being controlled by a group of transcription factors referred 34 to as epithelial -mesenchymal transition regulators (EMTRs): SIP1 [ [19,20] activities. In one of the studies, 50…”

“…These inhibitory effects were attributed to the blockade of NF-59 kB signaling by the tectorigenin [19]. It appears that tectorigenin has 60 immense anti-inflammatory properties that could attribute anti-61 cancer properties to the compound.…”