Tariquidar sensitizes multiple myeloma cells to proteasome inhibitors via reduction of hypoxia-induced P-gp-mediated drug resistance

Barbara Muz, Hubert D. Kusdono, Feda Azab, Pilar de la Puente, Cinzia Federico, Mark Fiala, Ravi Vij, Noha N. Salama, Abdel Kareem Azab

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Multiple myeloma (MM) presents a poor prognosis and high lethality of patients due to development of drug resistance. P-glycoprotein (P-gp), a drug-efflux transporter, is upregulated in MM patients post-chemotherapy and is involved in the development of drug resistance since many anti-myeloma drugs (including proteasome inhibitors) are P-gp substrates. Hypoxia develops in the bone marrow niche during MM progression and has long been linked to chemoresistance. Additionally, hypoxia-inducible transcription factor (HIF-1α) was demonstrated to directly regulate P-gp expression. We found that in MM patients P-gp expression positively correlated with the hypoxic marker, HIF-1α. Hypoxia increased P-gp protein expression and its efflux capabilities in MM cells in vitro using flow cytometry. We reported herein that hypoxia-mediated resistance to carfilzomib and bortezomib in MM cells is due to P-gp activity and was reversed by tariquidar, a P-gp inhibitor. These results suggest combining proteasome inhibitors with P-gp inhibition for future clinical studies.

Original languageEnglish
Pages (from-to)2916-2925
Number of pages10
JournalLeukemia and Lymphoma
Volume58
Issue number12
DOIs
StatePublished - Dec 2 2017

Keywords

  • Multiple myeloma
  • P-glycoprotein
  • drug resistance
  • hypoxia

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