Blockade of HSP70 by VER-155008 synergistically enhances bortezomib-induced cytotoxicity in multiple myeloma

Abstract

Proteasome inhibitor bortezomib is one of the most effective drugs currently available for the treatment of multiple myeloma (MM). However, the intrinsic and acquired resistance to bortezomib can limit its effectiveness. The activation of heat shock response has been characterized as a potential resistance mechanism protecting MM cells from bortezomib-induced cell death. In this study, in response to bortezomib therapy, we discovered that HSP70 is one of the most substantially upregulated heat shock proteins. In order to further explore approaches to sensitizing bortezomib-based treatment for MM, we investigated whether targeting HSP70 using a specific inhibitor VER-155008 combined with bortezomib could overcome the acquired resistance in MM. We found that HSP70 inhibitor VER-155008 alone significantly decreased MM cell viability. Moreover, the combination of VER-155008 and bortezomib synergistically induced MM cell apoptosis markedly in vitro. Notably, the combined treatment was found to increase the cleavage of PARP, an early marker of chemotherapy-induced apoptosis. Importantly, the reduction of anti-apoptotic Bcl-2 family member Bcl-2, Bcl-xL, and Mcl-1 and the induction of pro-apoptotic Bcl-2 family member BH3-only protein NOXA and Bim were confirmed to be tightly associated with the synergism. Finally, the ER stress marker CHOP (CCAAT-enhancer binding protein homologous protein), which can cause transcriptional activation of genes involved in cell apoptosis, was markedly induced by both VER-155008 and bortezomib. Taken together, our finding of a strong synergistic interaction between VER-155008 and bortezomib may support for combination therapy in MM patients in the future.

Inhibition of the Heat Shock Protein A (HSPA) Family Potentiates the Anticancer Effects of Manumycin A

“…Additionally, pan-HSPA inhibitors showed synergy with certain anticancer drugs. Their combination with bortezomib, a first-in-class proteasome inhibitor used as an oncological drug, showed synergistic effects on NSCLC cells in vitro [26] and in multiple myeloma in vitro and in vivo models [34,35]. Triple combination of HSPA inhibitor with cisplatin and 17-AGG, a HSPC inhibitor, showed a synergistic effect on bladder cancer cells [32].…”

A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer

“…Multiple myeloma patients often experience acquired resistance to bortezomib [138]. Hence, a combination of targeted therapies seems to be possible method, such as inhibiting the known compensatory mechanisms to proteasome inhibition, such as activation of HSP70/HSP90 molecular chaperones or autophagy [139][140][141], or targeting the NRF2-mutant p53-miRNA axis to counteract the proteasome inhibitor resistance [38,39].…”

Involvement of Alarmins in the Pathogenesis and Progression of Multiple Myeloma

“…These findings confirmed that sRAGE might be a protective role in bone progression [73]. Huang et al [74] investigated in MM cell lines (RPMI 8226, OPM2, and MM.1S) the effects of bortezomib, the first therapeutic proteasome inhibitor recommended for the first-line treatment in refractory, relapsed, and newly diagnosed MM. It has been postulated that the activation of the heat shock response may be one of the mechanisms by which MM does not respond or partially responds to bortezomib.…”