Proteasome and heat shock protein 70 (HSP70) inhibitors as therapeutic alternative in multiple myeloma

Abstract

HSP70 connects multiple signaling pathways that work synergistically to protect tumor cells from death by proteotoxic stress and represents a possible target to establish a new approach for multiple myeloma treatment. Therefore, bioluminescent cell lines RPMI8226-LUC-PURO and U266-LUC-PURO were treated with HSP70 (VER155008) and/or proteasome (bortezomib) inhibitors and immunodeficient mice were used for subcutaneous xenograft models to evaluate tumor growth reduction and tumor growth inhibition after treatment. Bioluminescence imaging was used to follow tumor response. Treatment with bortezomib showed ∼60% of late apoptosis in RPMI8226-LUC-PURO (without additional benefit of VER155008 in this cell line). However, U266-LUC-PURO showed ∼60% of cell death after treatment with VER155008 (alone or with bortezomib). RPMI8226-LUC-PURO xenograft presented tumor reduction by bioluminescence imaging after treatment with bortezomib, VER155008 or drug combination compared to controls. Treatment with bortezomib, alone or combined with VER155008, showed inhibition of tumor growth assessed by bioluminescence imaging after one week in both RPMI8226-LUC-PURO and U266-LUC-PURO cell lines when compared to controls. In conclusion, our study shows that the combination of proteasome and HSP70 inhibitors induced cell death in tumor cells in vitro (late apoptosis induction) and in vivo (inhibition of tumor growth) with special benefit in U266-LUC-PURO, bearing 17p deletion.

Functional redundancy of HSPA1, HSPA2 and other HSPA proteins in non-small cell lung carcinoma (NSCLC); an implication for NSCLC treatment

“…Our observation suggests that HSPAs form a highly redundant network of chaperones in NSCLC cells that might counteract the BTZ-induced proteotoxic stress. Results showing that pan-HSPA inhibition synergizes with proteasome arrest in breast cancer or multiple myeloma cells were also provided by others 41,57 . Accordingly, the concomitant inhibition of multiple HSPAs and proteasome function may represent a potent innovative approach to anticancer therapy.…”

Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

“…However, the next most prominent genes were those encoding several cytosolic HSP70 homologs: HSPA1A (HSP72 protein), HSPA6 (HSP70B), HSPA2 (HSP70-2), HSPA1L (HSP70-1L). This result supports previous analyses in MM 12,18 underscoring that pharmacologic blockade of both the proteasome and cytosolic HSP70s might be synergistic. We also observed a smaller cluster of proteasome subunits which included the ER-localized HSP70, HSPA5 (BiP/GRP78) ( Supplementary Fig.…”

Bortezomib promotes apoptosis of multiple myeloma cells by regulating HSP27

“…HSP90 inhibitors have been used in clinical trial for the treatment of MM (11)(12)(13)29). HSP70 inhibitors were also reported to induce MM tumor cell death (30). HSP27, a small HSP that is an aTP-independent chaperone protein, is reportedly overexpressed in several cancer types, including colorectal, breast and ovarian cancer, and and MM.…”