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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2017.8
- 수록면
- 567 - 576 (10page)
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초록· 키워드
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The Na+/H+ exchanger is responsible for maintaining the acidic tumor microenvironment through its promotion of the reabsorption of extracellular Na+ and the extrusion of intracellular H+. The resultant increase in the extracellular acidity contributes to the chemoresistance of malignant tumors. In this study, the chemosensitizing effects of cariporide, a potent Na+/H+-exchange inhibitor, were evaluated in human malignant mesothelioma H-2452 cells preadapted with lactic acid. A higher basal level of phosphorylated (p)-AKT protein was found in the acid-tolerable H-2452AcT cells compared with their parental acid-sensitive H-2452 cells. When introduced in H-2452AcT cells with a concentration that shows only a slight toxicity in H-2452 cells, cariporide exhibited growth-suppressive and apoptosis-promoting activities, as demonstrated by an increase in the cells with pyknotic and fragmented nuclei, annexin V-PE(+) staining, a sub-G0/G1 peak, and a G2/M phase-transition delay in the cell cycle. Preceding these changes, a cariporide-induced p-AKT down-regulation, a p53 up-regulation, an ROS accumulation, and the depolarization of the mitochondrial-membrane potential were observed. A pretreatment with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 markedly augmented the DNA damage caused by the cariporide, as indicated by a much greater extent of comet tails and a tail moment with in-creased levels of the p-histone H2A.X, p-ATMSer1981, p-ATRSer428, p-CHK1Ser345, and p-CHK2Thr68, as well as a series of pro-apoptotic events. The data suggest that an inhibition of the PI3K/AKT signaling is necessary to enhance the cytotoxicity toward the acid-tolerable H-2452AcT cells, and it underlines the significance of proton-pump targeting as a potential therapeutic strategy to overcome the acidic-microenvironment-associated chemotherapeutic resistance.
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참고문헌 (40)
참고문헌 신청
Alfarouk, K. O. / 2016 / Tumor metabolism, cancer cell transporters, and microenvironmental resistance / J. Enzyme Inhib. Med. Chem 31:859~866
Astanehe, A. / 2008 / Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer / J. Cell Sci 121:664~674
Caldecott, K. W. / 2007 / Mammalian single-strand break repair:mechanisms and links with chromatin / DNA Repair (Amst) 6:443~453
Casey, J. R. / 2010 / Sensors and regulators of intracellular pH / Nat. Rev. Mol. Cell Biol 11:50~61
De Milito, A. / 2005 / Tumor acidity, chemoresistance and proton pump inhibitors / Future Oncol 1:779~786
Astanehe, A. / 2008 / Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer / J. Cell Sci 121:664~674
Caldecott, K. W. / 2007 / Mammalian single-strand break repair:mechanisms and links with chromatin / DNA Repair (Amst) 6:443~453
Casey, J. R. / 2010 / Sensors and regulators of intracellular pH / Nat. Rev. Mol. Cell Biol 11:50~61
De Milito, A. / 2005 / Tumor acidity, chemoresistance and proton pump inhibitors / Future Oncol 1:779~786
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