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It has been demonstrated that the combination of cisplatin (DDP) with other chemotherapy drugs may significantly reduce drug resistance. Cinobufagin (CB) showed potent anti\u2010tumour effect against lung cancer. However, the relevance of CB and DDP resistance in lung cancer remains unclear. This article will study the effects of CB on reversing lung cell resistance. The apoptosis was rescued by flow cytometry analysis and TUNEL staining. The invasiveness was rescued by invasion assay. The mRNA and apoptosis\u2010related proteins were estimated by qRT\u2010PCR analysis and Western blot analysis, respectively. In\u00a0vivo antitumor activities were investigated by subcutaneous xenograft assay. The present study firstly demonstrated that the sensitivity of DDP in DDP\u2010resistant A549 (A549\/DDP) cells was enhanced when treated with CB. Moreover, CB combined with DDP weakened the proliferation and increased apoptosis of A549\/DDP cells. In addition, the expression level of Bcl\u20102 was increased, whereas Bax and caspase\u20103 were activated when A549\/DDP cells were treated with both drugs. After treatment with IGF1 or PMA and mixed drugs (CB\u2009+\u2009DDP), the expressions of P\u2010AKT, P\u2010PI3K, P\u2010MEK1\/2 and P\u2010ERK1\/2 were increased. Finally, the results of in\u00a0vivo experiments showed that the combination of DDP and CB significantly reduced the growth of tumours derived from A549\/DDP cells. The combination of CB and DDP can be considered an effective strategy to increase the sensitivity of DDP\u2010resistant lung cancer cells to DDP by inhibiting the PI3K\/AKT and MAPK\/ERK pathways.<\/jats:p>","DOI":"10.1111\/jcmm.70501","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T02:28:58Z","timestamp":1743215338000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cinobufagin Enhances the Sensitivity of Cisplatin\u2010Resistant Lung Cancer Cells to Chemotherapy by Inhibiting the PI3K\/AKT and MAPK\/ERK Pathways"],"prefix":"10.1111","volume":"29","author":[{"given":"Guangxin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery Second Hospital of Jilin University  Chang Chun People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center Second Hospital of Jilin University  Chang Chun People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4831-7595","authenticated-orcid":false,"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center Second Hospital of Jilin University  Chang Chun People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuwen","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Life Science Jilin Normal University  Si Ping People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangquan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center Second Hospital of Jilin University  Chang Chun People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6497-3387","authenticated-orcid":false,"given":"Yicun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Research Center Second Hospital of Jilin University  Chang Chun People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"3224","DOI":"10.3390\/cancers12113224","article-title":"Advances and Therapeutic Perspectives in Extended\u2010Stage Small\u2010Cell Lung Cancer","volume":"12","author":"Pierret T.","year":"2020","journal-title":"Cancers (Basel)"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"568939","DOI":"10.3389\/fonc.2020.568939","article-title":"Microbiota and Lung Cancer. 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