Tumor stressors induce two mechanisms of intracellular P-glycoprotein-mediated resistance that are overcome by lysosomal-targeted thiosemicarbazones

被引:46
作者
Al-Akra, Lina
Bae, Dong-Hun
Sahni, Sumit
Huang, Michael L. H.
Park, Kyung Chan
Lane, Darius J. R.
Jansson, Patric J. [1 ]
Richardson, Des R. [1 ]
机构
[1] Univ Sydney, Discipline Pathol, Mol Pharmacol & Pathol Program, Med Fdn Bldg K25, Sydney, NSW 2006, Australia
基金
英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
ISONICOTINOYL HYDRAZONE CLASS; MULTIDRUG-RESISTANCE; IRON CHELATORS; MEMBRANE PERMEABILIZATION; ANTITUMOR-ACTIVITY; DRUG-RESISTANCE; CANCER; HYPOXIA; DI-2-PYRIDYLKETONE; MODULATION;
D O I
10.1074/jbc.M116.772699
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Multidrug resistance (MDR) is a major obstacle in cancer treatment due to the ability of tumor cells to efflux chemotherapeutics via drug transporters (e.g. P-glycoprotein (Pgp; ABCB1)). Although the mechanism of Pgp-mediated drug efflux is known at the plasma membrane, the functional role of intracellular Pgp is unclear. Moreover, there has been intense focus on the tumor micro-environment as a target for cancer treatment. This investigation aimed to dissect the effects of tumor micro-environmental stress on subcellular Pgp expression, localization, and its role in MDR. These studies demonstrated that tumor micro-environment stressors (i.e. nutrient starvation, low glucose levels, reactive oxygen species, and hypoxia) induce Pgp-mediated drug resistance. This occurred by two mechanisms, where stressors induced 1) rapid Pgp internalization and redistribution via intracellular trafficking (within 1 h) and 2) hypoxia-inducible factor-1 alpha expression after longer incubations (4-24 h), which up-regulated Pgp and was accompanied by lysosomal biogenesis. These two mechanisms increased lysosomal Pgp and facilitated lysosomal accumulation of the Pgp substrate, doxorubicin, resulting in resistance. This was consistent with lysosomal Pgp being capable of transporting substrates into lysosomes. Hence, tumor micro-environmental stressors result in: 1) Pgp redistribution to lysosomes; 2) increased Pgp expression; 3) lysosomal biogenesis; and 4) potentiation of Pgp substrate transport into lysosomes. In contrast to doxorubicin, when stress stimuli increased lysosomal accumulation of the cytotoxic Pgp substrate, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone Dp44mT), this resulted in the agent overcoming resistance. Overall, this investigation describes a novel approach to overcoming resistance in the stressful tumor micro-environment.
引用
收藏
页码:3562 / 3587
页数:26
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