Journal
LEUKEMIA & LYMPHOMA
Volume 58, Issue 12, Pages 2916-2925Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/10428194.2017.1319052
Keywords
Multiple myeloma; drug resistance; P-glycoprotein; hypoxia
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Funding
- Washington University Institute of Clinical and Translational Sciences (ICTS) [UL1TR000448]
- National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH)
- National Cancer Institute of the NIH [U54CA199092]
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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-1) was demonstrated to directly regulate P-gp expression. We found that in MM patients P-gp expression positively correlated with the hypoxic marker, HIF-1. 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.
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