title: Efficacy of the HSP70 inhibitor PET-16 in multiple myeloma.
abstract: Multiple myeloma (MM) is a common and largely incurable blood cancer for which new treatment options are needed, as resistance to current modalities is an issue. Additionally, because this tumor type often resides in a hypoxic niche of the bone marrow, new therapeutics that remain effective even under hypoxic conditions are sought. Because of the secretory nature of MM cells they are uniquely under proteotoxic stress, and we hypothesized that these tumor cells may alleviate this stress by upregulating the major stress-induced cytosolic form of the chaperone HSP70. In this work we test the efficacy of the HSP70 inhibitor PET-16 for MM. We show that MM cell lines express significant levels of HSP70, and further that inhibition of HSP70 causes decreased viability and apoptosis, along with proteotoxic stress, as assessed by the accumulation of poly-ubiquitylated proteins. Importantly, we show that growth of these tumor cells under hypoxic conditions has no effect on the ability of PET-16 to be cytotoxic. The HSP70 inhibitor PET-16 should thus be considered further for pre-clinical analyses of efficacy in MM.
authors.affiliation: a Tumor Microenvironment and Metastasis; The Wistar Institute ; Philadelphia , PA USA.
authors.forename: Charvann K
authors.initials: CK
authors.lastname: Bailey
authors.affiliation: b Molecular and Cellular Oncogenesis; The Wistar Institute ; Philadelphia , PA USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Budina-Kolomets
authors.affiliation: b Molecular and Cellular Oncogenesis; The Wistar Institute ; Philadelphia , PA USA.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Murphy
authors.affiliation: a Tumor Microenvironment and Metastasis; The Wistar Institute ; Philadelphia , PA USA.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Nefedova
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D009861:Onium Compounds; D009943:Organophosphorus Compounds; C000608764:triphenyl(phenylethynyl)phosphonium
keywords: HSP70; hypoxia; multiple myeloma; proteasome; proteostasis