title: HSP70 inhibition reverses cell adhesion mediated and acquired drug resistance in multiple myeloma.
abstract: Heat shock proteins (HSPs) are a super family of highly conserved molecular chaperone proteins, which are induced in response to stress. HSP70 has been demonstrated to inhibit apoptosis induced by a number of chemotherapeutic agents. Previous investigations have suggested the development of drug resistance in multiple myeloma (MM) cells after adhesion to stroma. This study used MM cell lines and primary plasma cells to determine if HSP70 had a role in development of chemo resistance. Adhesion of MM cells to either bone marrow stromal cells or fibronectin (FN) enhanced HSP70 expression. Inhibition of the HSP70 expression decreased 8226 cell adhesion to stroma or FN and induced more apoptosis in FN-adhered 8226 cells than in suspension cultures at 24 h. Further, HSP70 inhibitors enhanced melphalan-induced apoptosis and reversed melphalan-induced cell adhesion-mediated drug resistance (CAM-DR) phenotype. In addition, compared to parental cells, KNK-437, a heat shock factor inhibitor caused more apoptosis in melphalan-resistant 8226/LR5 cells and sensitized them to melphalan. Primary CD138 positive cells showed high expression of HSPA4 mRNA, and KNK-437 caused apoptosis in these cells. In conclusion, our data suggest inhibition of HSP70, reduced adhesion and caused apoptosis of both acquired and de novo drug resistant MM cells.
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, Tuskegee University, Tuskegee, AL 36088, USA. ramadevi.nimmanapalli@gmail.com
authors.forename: Ramadevi
authors.initials: R
authors.lastname: Nimmanapalli
authors.forename: Elvira
authors.initials: E
authors.lastname: Gerbino
authors.forename: William S
authors.initials: WS
authors.lastname: Dalton
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: Melissa
authors.initials: M
authors.lastname: Alsina
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008558:Melphalan / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D010950:Plasma Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D005353:Fibronectins; D018840:HSP70 Heat-Shock Proteins; D008558:Melphalan