title: Combination treatment with triptolide and hydroxycamptothecin synergistically enhances apoptosis in A549 lung adenocarcinoma cells through PP2A-regulated ERK, p38 MAPKs and Akt signaling pathways.
abstract: Lung cancer is the leading cause of cancer death worldwide. Recently, two plant-derived drugs triptolide (TP) and hydroxycamptothecin (HCPT) both have shown broad-spectrum anticancer activities. Our previous study documented that combination treatment with these two drugs acted more effectively than mono-therapy, however, the molecular basis underlying the synergistic cytotoxicity remains poorly understood. In this study, we aimed to clarify the molecular mechanism of TP/HCPT anticancer effect in A549 lung adenocarcinoma cells, by investigating the involvement of phosphatase 2A (PP2A) and PP2A-regulated mitogen-activated protein kinases (MAPKs) and Akt signaling pathways. The results showed that TP and HCPT synergistically exerted cytotoxicity in the growth of A549 cells. Combinatorial TP/HCPT treatment significantly enhanced the activation of caspase-3 and -9, Bax/Bcl-2 ratio, release of cytochrome c from mitochondrial and subsequent apoptosis. While the Akt survival pathway was inhibited, ERK and p38 MAPKs were dramatically activated. Furthermore, the activity of PP2A was significantly augmented. Regulation of p38, ERK and Akt by PP2A was demonstrated, by using a specific PP2A inhibitor okadaic acid (OA). Finally, pharmacological inhibitors OA, SB203580, SP600125 and PD98059 confirm the role of PP2A and its substrates ERK, p38 MAPK and Akt in mediating TP/HCPT-induced apoptosis. Taken together, this study provides the first evidence for a synergistic TP/HCPT anticancer activity in A549 cells and also supports a critical role of PP2A and PP2A-regulated signaling pathways, providing new insight into the mode of action of TP/HCPT in cancer therapy.
authors.affiliation: Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou 310012, P.R. China.
authors.forename: Guanmin
authors.initials: G
authors.lastname: Meng
authors.affiliation: Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou 310012, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou 310012, P.R. China.
authors.forename: Kequn
authors.initials: K
authors.lastname: Chai
authors.affiliation: Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Medical College, Zhejiang University, Hangzhou 310016, P.R. China.
authors.forename: Suwen
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou 310012, P.R. China.
authors.forename: Fangqiong
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, Hangzhou 310012, P.R. China.
authors.forename: Kai
authors.initials: K
authors.lastname: Jiang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019703:Calcineurin / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D045744:Cell Line, Tumor / Q000187:drug effects; D004224:Diterpenes / Q000008:administration & dosage; D004357:Drug Synergism; D004852:Epoxy Compounds / Q000008:administration & dosage; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010616:Phenanthrenes / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; C001899:triptolide; D000077146:Irinotecan; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019703:Calcineurin; D002166:Camptothecin