Action of solamargine on TNFs and cisplatin-resistant human lung cancer cells.
A loss of TNF receptors expression has been found in advanced lung cancers, and human A549 lung adenocarcinoma cells are resistant to the cytotoxic effects of TNF-alpha and cisplatin. Here, the mechanisms of the drug resistance of A549 were extensively studied by gene modulation of the cells by solamargine (SM) which was isolated from Solanum incanum herb. SM induced morphological changes of chromatin condensation, DNA fragmentation, and sub-G(1) peak in a DNA histogram of A549 cells, indicating cell death by apoptosis. SM elevated the expressions of TNF-R1 and -R2 and overcame the resistance of A549 cells to TNF-alpha and -beta. The recruitment of TRADD, FADD, and activation of caspase-8 and -3 in SM-treated A549 cells evidenced the activation of TNFRs signal transduction. In addition, release of cytochrome c from mitochondria, down-expression of Bcl-2 and Bcl-x(L), up-regulation of Bax, and caspase-9 activities were observed in SM-treated A549 cells. Combinational treatment of SM and cisplatin synergistically enhanced caspase-8, -9, and -3 activities in A549 cells. Thus, SM sensitizes A549 cells through TNFRs and mitochondria-mediated pathways and may have anticancer potential against TNFs- and cisplatin-resistance lung cancer cells.
Liang
Chia-Hua
CH
Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Taiwan, ROC.
Liu
Li-Feng
LF
Shiu
Li-Yen
LY
Huang
Yu-Sheng
YS
Chang
Li-Ching
LC
Kuo
Kou-Wha
KW
D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D004273:DNA, Neoplasm / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms; D012991:Solanaceous Alkaloids / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D012991:Solanaceous Alkaloids; D014409:Tumor Necrosis Factor-alpha; C026609:beta-solamarine; D002945:Cisplatin