Tariquidar sensitizes multiple myeloma cells to proteasome inhibitors via reduction of hypoxia-induced P-gp-mediated drug resistance.
Tariquidar sensitizes multiple myeloma cells to proteasome inhibitors via reduction of hypoxia-induced P-gp-mediated drug resistance.
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DOI：
10.1080/10428194.2017.1319052
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发表时间：
2017-12
影响因子：
2.6
通讯作者：
Azab AK
中科院分区：
文献类型：
--
作者：
Muz B;Kusdono HD;Azab F;de la Puente P;Federico C;Fiala M;Vij R;Salama NN;Azab AK
多发性骨髓瘤（MM）由于耐药的发展，患者预后差，死亡率高。p -糖蛋白（P-gp）是一种药物外排转运蛋白，在MM患者化疗后上调，并参与耐药性的发展，因为许多抗骨髓瘤药物（包括蛋白酶体抑制剂）是p -糖蛋白底物。骨髓缺氧在MM进展过程中发生，长期以来与化疗耐药有关。此外，缺氧诱导转录因子（HIF-1α）可直接调节P-gp的表达。我们发现在MM患者中P-gp的表达与缺氧标志物HIF-1α呈正相关。用流式细胞术检测，缺氧可提高MM细胞P-gp蛋白的表达及其外排能力。我们在此报道缺氧介导的MM细胞对卡非佐米和硼替佐米的耐药是由于P-gp活性，并被P-gp抑制剂tariquar逆转。这些结果建议将蛋白酶体抑制剂与P-gp抑制剂联合应用于未来的临床研究。
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.
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DOI：
10.1158/1078-0432.ccr-10-1725
发表时间：
2011-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kelly RJ;Draper D;Chen CC;Robey RW;Figg WD;Piekarz RL;Chen X;Gardner ER;Balis FM;Venkatesan AM;Steinberg SM;Fojo T;Bates SE
通讯作者：
Bates SE
DOI：
10.1016/j.bbrc.2006.02.094
发表时间：
2006-04-21
影响因子：
3.1
作者：
Li, J;Shi, MX;Zhao, RCH
通讯作者：
Zhao, RCH
影响因子：
45.3
作者：
CORNELISSEN, JJ;SONNEVELD, P;LOKHORST, HM
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影响因子：
8.8
作者：
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通讯作者：
Woodcock, D M
影响因子：
12.8
作者：
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通讯作者：
Hawley, Robert G.