title: Calotropin from Asclepias curasavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells.
abstract: 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.
authors: College of Pharmacy, Jinan University, Guangzhou, 510632, PR China.
authors: En-Pan
authors: EP
authors: Mo
authors: College of Pharmacy, Jinan University, Guangzhou, 510632, PR China.
authors: Rong-Rong
authors: RR
authors: Zhang
authors: College of Pharmacy, Jinan University, Guangzhou, 510632, PR China.
authors: Jun
authors: J
authors: Xu
authors: College of Pharmacy, Jinan University, Guangzhou, 510632, PR China.
authors: Huan
authors: H
authors: Zhang
authors: College of Pharmacy, Jinan University, Guangzhou, 510632, PR China.
authors: Xiao-Xiong
authors: XX
authors: Wang
authors: College of Pharmacy, Jinan University, Guangzhou, 510632, PR China.
authors: Qiu-Tong
authors: QT
authors: Tan
authors: College of Pharmacy, Jinan University, Guangzhou, 510632, PR China.
authors: Fang-Lan
authors: FL
authors: Liu
authors: College of Pharmacy, Jinan University, Guangzhou, 510632, PR China. Electronic address: trwjiang@jnu.edu.cn.
authors: Ren-Wang
authors: RW
authors: Jiang
authors: College of Pharmacy, Jinan University, Guangzhou, 510632, PR China. Electronic address: csh5689@sina.com.
authors: Shao-Hui
authors: SH
authors: Cai
mesh_terms: D000072283:A549 Cells; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D031108:Asclepias / Q000737:chemistry*; D016203:CDC2 Protein Kinase; D002298:Cardenolides / Q000302:isolation & purification / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494826:BAX protein, human; C000595707:BCL2 protein, human; D002298:Cardenolides; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C546414:calotropin; D011065:Poly(ADP-ribose) Polymerases; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D048670:MAP Kinase Kinase 4; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D002945:Cisplatin
keywords: A549/CDDP cells; Apoptosis; Calotropin; Cell cycle arrest; JNK