Defective acidification in human breast tumor cells and implications for chemotherapy.
Defective acidification in human breast tumor cells and implications for chemotherapy.
复制标题
人乳腺肿瘤细胞中的酸化不足及其对化学疗法的影响。
DOI：
10.1084/jem.187.10.1583
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发表时间：
1998-05-18
影响因子：
15.3
通讯作者：
Simon, S M
中科院分区：
文献类型：
--
作者：
Altan, N;Chen, Y;Schindler, M;Simon, S M
多药耐药(MDR)是肿瘤治疗中的一个重要问题。化疗药物通过药物敏感细胞的细胞质和核质分布，但在耐药细胞中被排除在细胞核外，集中在细胞质细胞器中。弱碱性化疗药物(如蒽环类和长春花碱)应集中在酸性细胞器中。本文定量测定了MCF-7人乳腺癌细胞系各隔室的pH值，结果表明：(A)化疗药物阿霉素集中在耐药细胞的酸性细胞器中，而不是药物敏感细胞的酸性细胞器中；(B)在药物敏感细胞中，溶酶体和循环内含体不被酸化；(C)药物敏感细胞的胞浆比耐药细胞的胞浆酸性高0.4个pH单位；以及(D)用莫能菌素、巴菲霉素A1或刀豆素A破坏耐药细胞细胞器的酸化，足以将阿霉素的分布改变到药物敏感细胞中的分布，使细胞再次对化疗敏感。这些结果表明细胞器的酸化与耐药性有关，并与药物在酸性细胞器中的隔离以及随后通过分泌途径从细胞中排出的假说相一致。
Multidrug resistance (MDR) is a significant problem in the treatment of cancer. Chemotherapeutic drugs distribute through the cyto- and nucleoplasm of drug-sensitive cells but are excluded from the nucleus in drug-resistant cells, concentrating in cytoplasmic organelles. Weak base chemotherapeutic drugs (e.g., anthracyclines and vinca alkaloids) should concentrate in acidic organelles. This report presents a quantification of the pH for identified compartments of the MCF-7 human breast tumor cell line and demonstrates that (a) the chemotherapeutic Adriamycin concentrates in acidified organelles of drug-resistant but not drug-sensitive cells; (b) the lysosomes and recycling endosomes are not acidified in drug-sensitive cells; (c) the cytosol of drug-sensitive cells is 0.4 pH units more acidic than the cytosol of resistant cells; and (d) disrupting the acidification of the organelles of resistant cells with monensin, bafilomycin A1, or concanamycin A is sufficient to change the Adriamycin distribution to that found in drug-sensitive cells, rendering the cell vulnerable once again to chemotherapy. These results suggest that acidification of organelles is causally related to drug resistance and is consistent with the hypothesis that sequestration of drugs in acidic organelles and subsequent extrusion from the cell through the secretory pathways contribute to chemotherapeutic resistance.