title: Deoxypodophyllotoxin triggers necroptosis in human non-small cell lung cancer NCI-H460 cells.
abstract: Deoxypodophyllotoxin (DPT), a naturally occurring microtubule destabilizer, inhibits tubulin polymerization and causes cell cycle arrest at G2/M phase in tumor cells. However, the anti-tumor effect and specific mechanism of DPT in non-small cell lung cancer (NSCLC) are still poorly understood. In this study, we determined the anti-tumor effect and potential mechanism of DPT in the NSCLC cell line, NCI-H460 (H460). First, we demonstrated that DPT significantly inhibits the proliferation of H460 cells in vitro and the growth of H460 xenografts in vivo. In further studies, DPT triggered necroptosis in H460 cells with the following characteristics: (I) necrotic cell death morphology; (II) autophagy; (III) loss of plasma membrane integrity; (IV) loss of mitochondria membrane potential; (V) elevation of reactive oxygen species levels; and (VI) specific inhibition of necroptosis via a small molecule, necrostatin-1. This study also revealed that DPT has a similar effect towards the drug-sensitive cancer cell line, H460, and the drug-resistant cell line, H460/Bcl-xL. To our knowledge, this is the first report to document the induction of necroptosis by a microtubule-targeting agent to circumvent cancer drug resistance, thereby providing a new potential choice for clinical cancer therapy, especially drug-resistant cancer therapy.
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Wu
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
authors.forename: Huaqin
authors.initials: H
authors.lastname: Duan
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.forename: Mi
authors.initials: M
authors.lastname: Chen
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Qin
authors.initials: Q
authors.lastname: Gao
authors.forename: Yuming
authors.initials: Y
authors.lastname: Song
authors.forename: Xiong
authors.initials: X
authors.lastname: Zhu
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004365:Drugs, Chinese Herbal; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis / Q000473:pathology; D011034:Podophyllotoxin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; D017382:Reactive Oxygen Species; C014451:deoxypodophyllotoxin; D011034:Podophyllotoxin
keywords: Cancer; Deoxypodophyllotoxin; Drug resistance; Necroptosis