Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics.
Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics.
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人类ABC转运蛋白ABCG2/BCRP在化学上的表达：分子癌疗法的基本和临床观点。
DOI：
10.2147/pgpm.s38295
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发表时间：
2014
影响因子：
1.9
通讯作者：
Sugimoto Y
中科院分区：
文献类型：
--
作者：
Noguchi K;Katayama K;Sugimoto Y
三磷酸腺苷（ATP）结合盒（ABC）转运蛋白，如ABCB 1/P-糖蛋白（P-gp）和ABCG 2/乳腺癌耐药蛋白（BCRP），将各种结构上不相关的化合物转运出细胞。ABCG 2/BCRP被称为“半型”ABC转运蛋白，作为同二聚体发挥作用，并从细胞中转运抗癌药物，如伊立替康、7-乙基-10-羟基喜树碱（SN-38）、吉非替尼、伊马替尼、甲氨蝶呤和米托蒽醌。ABCG 2/BCRP的表达可赋予癌细胞多药耐药表型，并影响药物在正常组织中的吸收、分布、代谢和排泄，从而调节化疗药物的体内疗效。阐明ABCG 2/BCRP的底物偏好和结构关系对于我们理解其在化疗期间体内作用的分子机制至关重要。它的单核苷酸多态性也参与决定化疗药物的疗效，并且那些降低ABCG 2/BCRP功能活性的单核苷酸多态性可能与正常剂量的抗癌药物（ABCG 2/BCRP底物）的意外不良反应相关。重要的是，许多最近开发的分子靶向癌症药物，如酪氨酸激酶抑制剂，甲磺酸伊马替尼，吉非替尼等，也可以与ABCG 2/BCRP相互作用。ABCG 2/BCRP的功能性单核苷酸多态性和抑制剂都调节这些分子癌症治疗的体内药代动力学和药效学，因此ABCG 2/BCRP的药物遗传学是分子靶向化疗应用中的重要考虑因素。
Adenine triphosphate (ATP)-binding cassette (ABC) transporter proteins, such as ABCB1/P-glycoprotein (P-gp) and ABCG2/breast cancer resistance protein (BCRP), transport various structurally unrelated compounds out of cells. ABCG2/BCRP is referred to as a “half-type” ABC transporter, functioning as a homodimer, and transports anticancer agents such as irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), gefitinib, imatinib, methotrexate, and mitoxantrone from cells. The expression of ABCG2/BCRP can confer a multidrug-resistant phenotype on cancer cells and affect drug absorption, distribution, metabolism, and excretion in normal tissues, thus modulating the in vivo efficacy of chemotherapeutic agents. Clarification of the substrate preferences and structural relationships of ABCG2/BCRP is essential for our understanding of the molecular mechanisms underlying its effects in vivo during chemotherapy. Its single-nucleotide polymorphisms are also involved in determining the efficacy of chemotherapeutics, and those that reduce the functional activity of ABCG2/BCRP might be associated with unexpected adverse effects from normal doses of anticancer drugs that are ABCG2/BCRP substrates. Importantly, many recently developed molecular-targeted cancer drugs, such as the tyrosine kinase inhisbitors, imatinib mesylate, gefitinib, and others, can also interact with ABCG2/BCRP. Both functional single-nucleotide polymorphisms and inhibitory agents of ABCG2/BCRP modulate the in vivo pharmacokinetics and pharmacodynamics of these molecular cancer treatments, so the pharmacogenetics of ABCG2/BCRP is an important consideration in the application of molecular-targeted chemotherapies.