Calotropin from Asclepias curasavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells

• Published in: Biochemical and biophysical research communications 2016-09, Vol.478 (2), p.710-715
• Main Authors: Mo, En-Pan, Zhang, Rong-Rong, Xu, Jun, Zhang, Huan, Wang, Xiao-Xiong, Tan, Qiu-Tong, Liu, Fang-Lan, Jiang, Ren-Wang, Cai, Shao-Hui
• Format: Article
• Language: English
• Subjects: A549 Cells; A549/CDDP cells; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Asclepias; Asclepias - chemistry; bcl-2-Associated X Protein - agonists; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Calotropin; Cardenolides - isolation & purification; Cardenolides - pharmacology; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase 9 - genetics; Caspase 9 - metabolism; CDC2 Protein Kinase; Cell cycle arrest; Cisplatin - pharmacology; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - genetics; Cyclin-Dependent Kinase 2 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - agonists; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; G2 Phase Cell Cycle Checkpoints - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humans; JNK; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; Membrane Potential, Mitochondrial - drug effects; Mitochondria - drug effects; Mitochondria - metabolism; Plant Extracts - chemistry; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Proteolysis; Proto-Oncogene Proteins c-bcl-2 - agonists; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reactive Oxygen Species - metabolism; Signal Transduction; Tumor Suppressor Protein p53 - agonists; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.08.011

Calotropin (M11), an active compound isolated from Asclepias curasavica L., was found to exert strong inhibitory and pro-apoptotic activity specifically against cisplatin-induced resistant non-small cell lung cancer (NSCLC) cells (A549/CDDP). Molecular mechanism study revealed that M11 induced cell cycle arrest at the G2/M phase through down-regulating cyclins, CDK1, CDK2 and up-regulating p53 and p21. Furthermore, M11 accelerated apoptosis through the mitochondrial apoptotic pathway which was accompanied by increase Bax/Bcl-2 ratio, decrease in mitochondrial membrane potential, increase in reactive oxygen species production, activations of caspases 3 and 9 as well as cleavage of poly ADP-ribose polymerase (PARP). The activation and phosphorylation of JNK was also found to be involved in M11-induced apoptosis, and SP610025 (specific JNK inhibitor) partially prevented apoptosis induced by M11. In contrast, all of the effects that M11 induce cell cycle arrest and apoptosis in A549/CDDP cells were not significant in A549 cells. Drugs with higher sensitivity against resistant tumor cells than the parent cells are rather rare. Results of this study supported the potential application of M11 on the non-small lung cancer (NSCLC) with cisplatin resistance. •This is the first report revealing the anti-tumor bioactivity of M11 on A549 and A549/CDDP cells. And A549/CDDP cells are about 100 times more sensitive than A549 cells to M11 treatment.•M11 induces cell cycle arrest at the G2/M phase in A549/CDDP cells.•M11 triggers JNK-mediated apoptosis via the mitochondrial apoptotic pathway in A549/CDDP cells.