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Leuk Lymphoma. 2017 Dec;58(12):2916-2925. doi: 10.1080/10428194.2017.1319052. Epub 2017 May 16.

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

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a Department of Radiation Oncology, Cancer Biology Division , Washington University in Saint Louis School of Medicine , St. Louis , MO , USA.
b Department of Pharmaceutical and Administrative Sciences , St. Louis College of Pharmacy , St. Louis , MO , USA.
c Section of Stem Cell Transplant and Leukemia, Division of Medical Oncology , Washington University in Saint Louis School of Medicine , St. Louis , MO , USA.
d Department of Pharmaceutics and Industrial Pharmacy , Cairo University Faculty of Pharmacy , Cairo , Egypt.


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.


Multiple myeloma; P-glycoprotein; drug resistance; hypoxia

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