title: Xanthatin induces cell cycle arrest at G2/M checkpoint and apoptosis via disrupting NF-κB pathway in A549 non-small-cell lung cancer cells.
abstract: Xanthatin, a natural sesquiterpene lactone, has significant antitumor activity against a variety of cancer cells, yet little is known about its anticancer mechanism. In this study, we demonstrated that xanthatin had obvious dose-/time-dependent cytotoxicity against the human non-small-cell lung cancer (NSCLC) cell line A549. Flow cytometry analysis showed xanthatin induced cell cycle arrest at G2/M phase. Xanthatin also had pro-apoptotic effects on A549 cells as evidenced by Hoechst 33258 staining and annexin V-FITC staining. Mechanistic data revealed that xanthatin downregulated Chk1, Chk2, and phosphorylation of CDC2, which contributed to the cell cycle arrest. Xathatin also increased total p53 protein levels, decreased Bcl-2/Bax ratio and expression of the downstream factors procaspase-9 and procaspase-3, which triggered the intrinsic apoptosis pathway. Furthermore, xanthatin blocked phosphorylation of NF-κB (p65) and IκBa, which might also contribute to its pro-apoptotic effects on A549 cells. Xanthatin also inhibited TNFa induced NF-κB (p65) translocation. We conclude that xanthatin displays significant antitumor effects through cell cycle arrest and apoptosis induction in A549 cells. These effects were associated with intrinsic apoptosis pathway and disrupted NF-κB signaling. These results suggested that xanthatin may have therapeutic potential against NSCLC.
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Junshan
authors.initials: J
authors.lastname: Ruan
authors.forename: Linggeng
authors.initials: L
authors.lastname: Yan
authors.forename: Weidong
authors.initials: W
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
authors.forename: Aiyun
authors.initials: A
authors.lastname: Wang
authors.forename: Yin
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; C022186:xanthatin