Bortezomib Targets the Caspase-Like Proteasome Activity in Cervical Cancer Cells, Triggering Apoptosis That Can be Enhanced by Nelfinavir

Abstract

The occurrence of chemoresistance is a serious problem in the treatment of cancer, urging the need for second and third-line treatment options that rely on different cell death pathways to overcome previously acquired resistance mechanisms. The inhibition of proteasomal activity by specific proteasome inhibitors or cross-reactivity of certain protease inhibitors with proteasomal enzymes recently became of interest because of the anti-tumoral properties of these agents. We tested the proteasome inhibitor bortezomib and the HIV protease inhibitor nelfinavir on human cervical cancer cells. Both drugs induced cell cycle arrest in cervical cancer cells, as reflected by marked changes in the expression of cell cycle-regulatory cyclins and ensuing mitochondrial-independent apoptosis. Upregulation of the molecular chaperone BiP and the cell stress marker ATF3 indicated induction of the unfolded protein response (UPR) as the main cause of apoptosis induced by these drugs in cervical cancer cells. Unlike in leukemia cells, bortezomib mainly inhibited the caspase-like activity of the proteasome in cervical cancer cells. Nelfinavir exhibited no effects on proteasomal activity in cervical cancer cells and leukemia cells. Although both bortezomib and nelfinavir acted on cisplatin-resistant cervical cancer cells (SiHa), neither of the drugs induced a sensitization to cisplatin treatment. Instead, both drugs could effectively be combined with each other, and enhanced the efficacy of an apoptosis-inducing TRAIL receptor antibody. These results suggest that both bortezomib and nelfinavir are effective agents against chemoresistant cervical cancer cells and might be of interest for clinical studies on cervical cancer patients with recurrent or metastatic cancer.

Induction of apoptosis in cervical cancer cells by the duplex drug 5-FdU–ECyd, coupling 2′-deoxy-5-fluorouridine and 3′-C-ethinylcytidine

“…In conclusion, we demonstrate that 5-FdU-ECyd is able to induce apoptotic cell death in cisplatin-sensitive (HeLa, CaSki, Me180) and cisplatin-resistant (SiHa) [22] cervical cancer cells. This highly active compound may therefore be effective in advanced, treatment-resistant cervical cancers and warrants further investigation in vivo and in clinical trials.…”

Nelfinavir, an HIV protease inhibitor, induces apoptosis and cell cycle arrest in human cervical cancer cells via the ROS-dependent mitochondrial pathway

“…These findings, taken together, suggest that mitochondriaderived ROS play a key role both in Nelfinavir-induced cervical cancer cell apoptosis and G1 cell cycle arrest. Notably, Bruning et al reported that Nelfinavir could not disrupt the mitochondrial membrane potential in the HeLa cells [35]. The discrepancy is possibly because the different storage methods, culture times and passage numbers were used.…”

Proteasome inhibition by quercetin triggers macroautophagy and blocks mTOR activity

“…3a). Bortezomib is a clinically approved proteasome inhibitor that has previously been shown to induce the unfolded protein response (UPR) in epithelial cancer cells, in part associated with ER stress, but primarily caused by a cytosolic cell stress mechanism (Brüning et al 2008;Brüning et al 2011). These similarities to bortezomib prompted us to test whether quercetin could act as a proteasome inhibitor.…”