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Role of Prosurvival Molecules in the Action of Lidamycin toward Human Tumor cells

Biomedical and Environmental Sciences 2009年第3期22卷 244-252页

作者： A-JING YANG WEI-WEI SHI YONG LI ZHEN WANG RONG-GUANG SHAO DIAN-DONG LI QI-YANG HE Institute of Medicinal Biotechnology Peking Union Medical College and Chinese Academy of Medical Sciences Beijing 100050 China

Objective Lidamycin, an enediyne antibiotic, leads to apoptosis and mitotic cell death of human tumor cells at high and low concentrations. The reason why tumor cells have distinct responses to lidamycin remains elusive. This study was to elucidate if cellular prosurvival molecules are involved in these responses. Methods Cleavage of chromatin and DNA was observed by chromatin condensation and agarose gel electrophoresis. Accumulation of rhodamine 123 in lidamycin-treated cells was assayed by flow cytometry. cell multinucleation was detected by staining with Hoechst 33342. Western blot and senescence-associated β-galactosidase （SA-β-gal） staining were used to analyze protein expression and senescence-like phenotype, respectively. Results SIRT1 deacetylase remained unchanged in 0.5 nmol/L lidamycin whereas cleavage occurred when apoptosis was induced by lidamycin. Increased FOXO3a, SOD-1 and SOD-2 expression and transient phosphorylation of ERK were detected after exposure of human hepatoma BEL-7402 cells to 0.5 nmol/L lidamycin. High expressions of SIRT1 and Akt were found in colon carcinoma HCT116 p53 knock-out cells exposed to lidamycin. Degradation of PARP and p53 by lidamycin as a substitute for SIRT1 and Akt was confirmed with caspase inhibitor Q-VD-OPh and proteasome inhibitor MG132. Resistance to lidamycin-induced DNA cleavage was observed in breast cancer doxorubicin-resistant MCF-7 cells. This was not induced by P-glycoprotein as no accumulation of rhodamine 123 was detected in the resistant cells following exposure to lidamycin. In contrast to sensitive MCF-7 cells, a lower multinucleation rate for the resistant cells was measured following exposure to equal concentrations of lidamycin. Conclusions cellular prosurvival molecules, such as SIRTI, Akt, SOD-1, SOD-2 and other unknown factors can influence the action of lidamycin on human tumor cells.

关键词： Lidamycin Prosurvival molecules SIRTI deacetylase Apoptosis mitotic cell death Multidrug resistance

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Effect of Lidamycin on Telomerase Activity in Human Hepatoma BEL-7402 cells

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Biomedical and Environmental Sciences 2007年第3期20卷 189-197页

作者： RUI-JUAN GAO YUE-XIN LIANG DIAN-DONG LI HONG-YIN ZHANG YONG-SU ZHEN Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China Peking University Hospital Beijing 100871 China

Objective To investigate the effect of lidamycin （LDM） on telomerase activity in human hepatoma BEL-7402 cells under the condition of LDM inducing mitotic cell death and senescence. Methods Chromatin condensation was detected by co-staining with Hoechst 33342 and PI. cell multinucleation was observed by Giemsa staining and genomic DNA was separated by agarose gel electrophoresis. Fluorescent intensity of Rho123 was determined for mitochondrial membrane potential. MTT assay and SA-13-gal staining were employed to analyze the senescence-like phenotype. The expression of proteins was analyzed by Western blot. Telomerase activity was assayed by telomerase PCR-ELISA. Results mitotic cell death occurred in LDM-treated cells characterized by unique and atypical chromatin condensation, multinucleation and increased mitochondrial membrane potential. However, no apoptotic bodies or DNA ladders were found. In addition, apoptosis-related proteins remained nearly unaltered. Senescence-like phenotype was identified by increased and elongated size of cells, growth retardation, enhanced SA-13-gal activity and the changes of senescence-related protein expression. Telomerase activity markedly decreased （P〈0.01） in LDM-treated hepatoma BEL-7402 cells. Conclusion mitotic cell death and senescence could be triggered simultaneously or sequentially after exposure of hepatoma BEL-7402 cells to LDM. The decrease in telomerase activity may play a key role in the defective mitosis and aging morphology. Further investigation of detailed mechanism is needed.

关键词： LDM mitotic cell death cellular senescence Telomerase activity

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