HSP70 inhibition reverses cell adhesion mediated and acquired drug resistance in multiple myeloma

Ramadevi Nimmanapalli, Elvira Gerbino, William S. Dalton, Varsha Gandhi, Melissa Alsina

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)551-561
Number of pages11
JournalBritish Journal of Haematology
Volume142
Issue number4
DOIs
Publication statusPublished - Aug 2008

Keywords

  • Adhesion
  • Cell adhesion mediated resistance
  • Drug resistance
  • HSP70
  • Multiple myeloma

ASJC Scopus subject areas

  • Hematology

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