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Kim, Jung-Ae,Kang, Young Shin,Jung, Mi-Wha,Kang, Ga-Hwa,Lee, Sun Hee,Lee, Yong Soo 영남대학교 약품개발연구소 2000 영남대학교 약품개발연구소 연구업적집 Vol.10 No.-
Apoptosis appears to be implicated in the pathogenesis and therapeutic applications of cancer. In this study we investigated the induction of apoptosis by 4-aminopyri-dine(4-AP), a K^(+) channel blocker, and its mechanism in HepG2 human hepatoblastoma cells. 4-AP reduced cell viability and induced DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. In addition, 4-AP induced a sustained increase in intracellular Ca^(2+) con-centration, which was completely inhibited by the extra-cellular Ca^(2+) chelation with EGTA. 4-AP also induced Mn^(2+) influx, indicating that the 4-AP-induced increased intracellular Ca^(2+) levels were due to activation of Ca^(2+) influx pathway. 4-AP also depolarized membrane poten-tial that was measured by using di-O-C_(5)(3), a voltage-sensitive fluorescent dye. 4-AP-induced Ca^(2+) influx was significantly inhibited not by voltage-operative Ca^(2+) channel blockers(nifedipine or verapamil), but by flufen-amic acid(FA), a known nonselective cation channel blocker. Quantitative analysis of apoptosis by the flow cytometry revealed that treatment with either FA or BAP-TA, an intracellular Ca^(2+) chelator, significant inhibited the 4-AP-induced apoptosis. Taken together, these re-sults suggest that the observed 4-AP-induced apoptosis in the HepG2 cells may result from Ca^(2+) influx through the activation of voltage-sensitive Ca^(2+)-permeable non-selective cation channels. These results further suggest that membrane potential change by modulation of K^(+) channel activity may be involved in the mechanism of apoptosis in human hepatoma cells.
Kim, Jung-Ae,Kang, Young Shin,Jung, Mi-Wha,Lee, Sun Hee,LEE, Yong Soo 영남대학교 약품개발연구소 2000 영남대학교 약품개발연구소 연구업적집 Vol.10 No.-
The signaling mechanism of tamoxifen(TAM)-induced apoptosis was investigated in HepG2 human hepatoblastoma cells which do not express the estrogen receptor(ER). TAM induced cytotoxicity and DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. TAM increased the intracellular concentration of Ca^(2+). This effect was completely inhibited by the extracellular Ca^(2+) chelation with EGTA. TAM also induced a Mn^(2+) inflex, indicating that TAM activated Ca^(2+) influx pathways. This action of TAM was significantly inhibited by flufenamic acid(FA), a known non-selective cation channel blocker. Quantitative analysis of apoptosis by flow cytometry revealed that treatment with either FA or BAPTA, an intracellular Ca^(2+) chelator, significantly inhibited TAM-induced apoptosis. These results suggest that intracellular Ca^(2+) signals may play a central role in the mechanism of the TAM-induced apoptotic cell death in ER-negative HepG2 cells. ⓒ1999 Elsevier Science Ireland Ltd. All rights reserved.
Lee, Yong Soo,Ha, Jeoung-Hee,Yong, Chul Soon,Lee Dong-Ung,Huh, Keun,Kang, Young Shin,Lee, Sun Hee,Jung, Mi-Wha,Kim, Jung-Ae 영남대학교 약품개발연구소 1999 영남대학교 약품개발연구소 연구업적집 Vol.9 No.-
The inhibitory effects of the constituent of Gastrodia elata BI. (GE) on glutamate-induced apoptosis in human neuronal cells were investigated using IMR32 human neuroblastoma cells. Glutamate (GLU) induced DNA fragmentation, a hallmark of apoptosis, in a dose-dependent manner. GLU also induced a slow and sustained increase in intracellular Ca^(2+) concentration. Treatment with EGTA, an extracellular Ca^(2+) chelator, in a nominal Ca^(2+) -free buffer solution abolished the CLU-induced intracellular Ca^(2+) increase, indicating that GLU stimulated Ca^(2+) influx pathway in the IMR32 cells. BAPTA, an intracellular Ca^(2+) chelator, significantly inhibited the GLU-induced apoptosis assessed by the flow cytometry measuring hypodiploid DNA content indicative of apoptosis, implying that intracellular Ca^(2+) rise may mediate the apoptotic action of GLU. Vanillin (VAN) and p-hydroxybenzaldehyde(p-HB), known constituents of GE, significantly inhibited both intracellular Ca^(2+) rise and apoptosis induced by GLU. These results suggest that the apoptosis-inhibitory actions of the consti-tuent of GE may account, at least in part, for the basis of their antiepileptic activities. These results further suggest that intracellular Ca^(2+) signaling pathway may be a molecular target of the constituents of GE.