title: Proteotoxic stress targeted therapy (PSTT): induction of protein misfolding enhances the antitumor effect of the proteasome inhibitor bortezomib.
abstract: Proteotoxic stress (PS) is generated in cells under a variety of conditions involving accumulation of misfolded proteins. To avoid the toxicity of unmitigated PS, cells activate the heat shock response (HSR). HSR involves upregulation of factors such as ubiquitin and the non-housekeeping chaperone Hsp70 which assist with metabolism of aberrant proteins. The PS-HSR axis is a potential anticancer treatment target since many tumor cells display constitutive PS and dependence on HSR due to their rapid rates of proliferation and translation. In fact, induction of PS via stimulation of protein misfolding (hyperthermia), inhibition of proteasomes (bortezomib) or inhibition of Hsp90 (geldanamycin) have all been considered or used for cancer treatment. We found that combination of bortezomib with an inducer of protein misfolding (hyperthermia or puromycin) resulted in enhanced PS. HSR was also induced, but could not mitigate the elevated PS and the cells died via largely p53-independent apoptosis. Thus, combination treatments were more cytotoxic in vitro than the component single treatments. Consistent with this, combination of non-toxic doses of puromycin with bortezomib significantly increased the antitumor activity of bortezomib in a mouse model of multiple myeloma. These results provide support for using combination treatments that disrupt the balance of PS and HSR to increase the therapeutic index of anticancer therapies.
authors: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors: Nickolay
authors: N
authors: Neznanov
authors: Andrei P
authors: AP
authors: Komarov
authors: Lubov
authors: L
authors: Neznanova
authors: Patricia
authors: P
authors: Stanhope-Baker
authors: Andrei V
authors: AV
authors: Gudkov
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004357:Drug Synergism; D045325:HCT116 Cells; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis; D006367:HeLa Cells; D018869:Heat-Shock Response / Q000187:drug effects; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D057165:Proteostasis Deficiencies / Q000139:chemically induced / Q000378:metabolism*; D011691:Puromycin / Q000008:administration & dosage / Q000494:pharmacology; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D001897:Boronic Acids; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011691:Puromycin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex