Cariporide Enhances the DNA Damage and Apoptosis in Acid-tolerable Malignant Mesothelioma H-2452 Cells
- Abstract
- 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-G(0)/G(1) peak, and a G(2)/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 increased levels of the p-histone H2A.X, p-ATM(Ser1981), p-ATR(Ser428), p-CHK1(Ser345), and p-CHK2(Thr68), 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.
- All Author(s)
- Y. J. Lee
; J. H. Bae
; S. A. Kim
; S. H. Kim
; K. M. Woo
; H. S. Nam
; M. K. Cho
; S. H. Lee
- Issued Date
- 2017
- Type
- Article
- Keyword
- LY294002; cariporide; malignant mesothelioma; p53; phosphatidylinositol-3-kinase
- ISSN
- 1016-8478
- Citation Title
- Mollecules and Cells
- Citation Volume
- 40
- Citation Number
- 8
- Citation Start Page
- 567
- Citation End Page
- 576
- Language(ISO)
- eng
- DOI
- 10.14348/molcells.2017.0059
- URI
- http://schca-ir.schmc.ac.kr/handle/2022.oak/1084
- 공개 및 라이선스
-
- 파일 목록
-
Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.