Sensitization of multidrug-resistant cancer cells to Hsp90 inhibitors by NSAIDs-induced apoptotic and autophagic cell death

Abstract

NSAIDs (non-steroidal anti-inflammatory drugs) have potential use as anticancer agents, either alone or in combination with other cancer therapies. We found that NSAIDs including celecoxib (CCB) and ibuprofen (IBU) significantly potentiated the cytotoxicity of Hsp90 inhibitors in human multidrug-resistant (MDR) cells expressing high levels of mutant p53 (mutp53) protein and P-glycoprotein (P-gp), and reversed Hsp90 inhibitor resistance caused by activation of heat shock factor 1 (HSF1) and by up-regulation of heat shock proteins (Hsps) and P-gp. Inhibition of Akt/mTOR and STAT3 pathways by CCB induced autophagy, which promoted the degradation of mutp53, one of Hsp90 client proteins, and subsequently down-regulated HSF1/Hsps and P-gp. Inhibition of autophagy prevented mutp53 degradation and CCB-induced apoptosis, and inhibition of caspase-3-mediated apoptotic pathway by Z-DEVD-FMK did not completely block CCB-induced cell death in MDR cells, suggesting that autophagic and apoptotic cell death may contribute to CCB-induced cytotoxicity in MDR cells. Furthermore, CCB and IBU suppressed Hsp90 inhibitor-induced HSF1/Hsp70/P-gp activity and mutp53 expression in MDR cells. Our results suggest that NSAIDs can be used as potential Hsp90 inhibitor chemosensitizers and reverse resistance of MDR cells to Hsp90 inhibitors via induction of apoptosis and autophagy. These results might enable the use of lower, less toxic doses of Hsp90 inhibitors and facilitate the design of practically applicable, novel combination therapy for the treatment of MDR cancer.

Nonsteroidal Anti-inflammatory Drugs Sensitize CD44-Overexpressing Cancer Cells to Hsp90 Inhibitor Through Autophagy Activation

“…Recently, Mcl-1, a downstream target of STAT3, has been reported to have an important role in the regulation of autophagy, and the degradation of Mcl-1 relieves Beclin-1 50,51 , indicating that STAT3/Mcl-1 pathway is also involved in regulation of autophagy. Previously, we also reported that autophagy inducing the ability of NSAIDs through inhibition of Akt/mTOR and STAT3 pathways was effective for the sensitization of MDR cells to 17-AAG 52 . Similarly, the current study showed that activation of AMPK and inhibition of Akt/mTOR/p70S6K/4EBP1 signaling axis and STAT3/Mcl-1 pathways participate in NSAID-induced autophagy in CD44 high K562 cells.…”

Aspirin Induced Glioma Apoptosis through Noxa Upregulation

“…Monotherapy and combinatory therapy with COX inhibitors have been reported in the treatment of various types of cancers. Cell cycle progression, migration, invasion, angiogenesis, autophagy, apoptosis, and resistance can be classified as biochemical events that are vulnerable to either direct or indirect actions of COX inhibitors [ 4 , 5 , 6 , 7 , 8 ]. While COX inhibitors appear to induce adverse effects and off-target actions, they also display chemo-preventive properties that warrant further investigation.…”

<p>Regulation of Autophagy by Non-Steroidal Anti-Inflammatory Drugs in Cancer</p>

“…Under strong cellular ER stress, NSAID-induced autophagy results in induction of apoptosis. [75][76][77][78] Dimethyl celecoxib, a derivative of celecoxib, effectively inhibits colon cancer, triple-negative breast cancer, and glioma cell growth through induction of ER stress and in combination with chloroquine, bortezomib, and radiotherapy to play synergic effects on the induction of tumor cell autophagy. 79,80 Celecoxib targets the pro-oxidative state of highly metastatic cancer cells and cancer stem cells and drives excess ROS production in these cells, resulting in cell death.…”

“…94 Furthermore, sulindac sulfide increased the sensitivity of multidrug-resistant cancer cells to Hsp90 inhibitors through the induction of autophagy. 75 Sodium salicylate inhibited the growth of A549 cells through the transformation from tumor necrosis to tumor-suppressive autophagy. 95 Moreover, Bauvy et al reported that inhibition of autophagy increased sulindac sulfide-induced apoptosis in HT-29 cells.…”