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Although there has been an increasing amount of research regarding its anticancer effects, the association between oxidative stress, genotoxicity and the cell cycle arrest induced by PLB still remains unclear. Therefore, it is important to investigate their potential connections and the involvement of DNA damage and the ataxia telangiectasia mutated protein (ATM)-p53 signaling pathway in PLB\u2019s anticancer mechanism. The present study showed that PLB exposure significantly reduced HCC cell viability and colony formation. In addition, PLB-induced G2\/M cell cycle arrest, oxidative stress, and DNA damage was detected, which could be almost blocked by NAC pretreatment. PLB could trigger a DNA damage response by activating cell cycle checkpoints such as ATM, checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2) and p53. Meanwhile, the key modulator of the G2\/M transition factor, Cell Division Cycle 25C (cdc25C), was significantly downregulated in an ROS-dependent manner. Furthermore, pretreatment with ATM and p53 inhibitors (KU55933 and Pifithrin-\u03b1) could reduce the occurrence of G2\/M cell cycle arrest by inhibiting the activation of the ATM-p53 pathway. Taken together, these results indicate that ROS-mediated oxidative stress plays a key role in PLB-induced G2\/M cell cycle arrest mediated by the ATM-p53 pathway.<\/jats:p>","DOI":"10.3390\/ijms24076279","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T05:34:30Z","timestamp":1679895270000},"page":"6279","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Plumbagin Exhibits Genotoxicity and Induces G2\/M Cell Cycle Arrest via ROS-Mediated Oxidative Stress and Activation of ATM-p53 Signaling Pathway in Hepatocellular Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Huan","family":"Liu","sequence":"first","affiliation":[{"name":"Laboratory of Medical Molecular Biology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530024, China"},{"name":"Guangxi Key Laboratory of Molecular Biology of Preventive Medicine of Traditional Chinese Medicine, Nanning 530024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenchao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research Center for Non-Food Biorefinery, Guangxi Academy of Science, Nanning 530001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijie","family":"Jin","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Molecular Biology of Preventive Medicine of Traditional Chinese Medicine, Nanning 530024, China"},{"name":"Department of Physiology, Guangxi University of Chinese Medicine, Nanning 530200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Molecular Biology of Preventive Medicine of Traditional Chinese Medicine, Nanning 530024, China"},{"name":"Department of Physiology, Guangxi University of Chinese Medicine, Nanning 530200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Liang","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Molecular Biology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530024, China"},{"name":"Guangxi Key Laboratory of Molecular Biology of Preventive Medicine of Traditional Chinese Medicine, Nanning 530024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0768-4690","authenticated-orcid":false,"given":"Yanfei","family":"Wei","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Molecular Biology of Preventive Medicine of Traditional Chinese Medicine, Nanning 530024, China"},{"name":"Department of Physiology, Guangxi University of Chinese Medicine, Nanning 530200, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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