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Cisplatin and its derivatives are commonly used in classical chemotherapy, but their therapeutic efficacy is limited, and they came with significant side effects. The targeted therapies and immunotherapy have improved survival rates for certain groups of patients. However, overall survival for NSCLC remains very low, which contributes to the high mortality rate. Thus, the search for effective and affordable drugs is ongoing. In this context, ruthenium-based complexes have been extensively studied as promising anticancer agents. In our previous studies, three ruthenium\u00ad(II) complexes containing cinnamic acid derivatives with ligands were synthesized and characterized. We demonstrated that the complex [Ru\u00ad(trans-4-(trifluoromethyl)\u00adcinnam)\u00ad(dppb)\u00ad(bipy)]\u00adPF6 effectively inhibited the proliferation of melanoma cells with either an activating N-Ras mutation or a TP53 inactivation mutation. Therefore, in this study, we aimed to evaluate the antitumor potential of complex [Ru\u00ad(3,4-cinnam)\u00ad(dppb)\u00ad(bipy)]\u00adPF6, named CINNAM, against nonsmall cell lung cancer cells A549 (TP53 wild type; K-Ras mutated) and H1299 (TP53 mutated; N-Ras mutated). CINNAM selectively targeted cancer cells over normal cells, with A549 cells showing higher sensitivity to the CINNAM compared to H1299 cells. CINNAM effectively reduced the proliferation of A549 cells by inducing cell cycle arrest at the G0\/G1 phase. CINNAM modulated the expression profiles of key cell cycle regulators, CDKN1A, CCND1, and CCNE2. Further, we demonstrated that the cytotoxic activity of CINNAM is linked to its pro-oxidant and pro-apoptotic properties. The interactions of the complex with ct-DNA (calf thymus DNA) were analyzed, and based on the Kb value, the complex present intermediate affinity for DNA. In conclusion, CINNAM exhibits potent antiproliferative and pro-apoptotic effects on NSCLC cells, surpassing those observed with cisplatin.<\/jats:p>","DOI":"10.1021\/acsomega.5c00526","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T16:31:11Z","timestamp":1751387471000},"page":"28956-28968","source":"Crossref","is-referenced-by-count":4,"title":["Ruthenium(II) Complex\nwith 3,4-Methylenedioxy Cinnamic\nAcid Induces Cell Cycle Arrest at G0\/G1 and Apoptosis via ROS Generation\nand Bioenergetics Disruption in Non-Small Cell Lung Cancer Cells"],"prefix":"10.1021","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9133-2198","authenticated-orcid":true,"given":"Guilherme\nA\u0301lvaro","family":"Ferreira-Silva","sequence":"first","affiliation":[{"name":"Federal University of Alfenas , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4979-6022","authenticated-orcid":true,"given":"Caio Cesar","family":"Candido","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graciana Yokota","family":"Garavelli","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7015-5065","authenticated-orcid":true,"given":"Carolina","family":"Girotto Pressete","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester Siqueira","family":"Caixeta","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelica Ellen","family":"Graminha","sequence":"additional","affiliation":[{"name":"Sa\u0303o Paulo State University , , , ,","place":["Araraquara, Sa\u0303o Paulo, Brazil, 14800-060"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u0301lia Imaculada Fraza\u0303o","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2726-1265","authenticated-orcid":true,"given":"Anto\u0302nio\nCarlos","family":"Doriguetto","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8796-1426","authenticated-orcid":true,"given":"Marisa","family":"Ionta","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Ferro Aissa","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"issue":"10445","key":"2026081812114963700_cit1","doi-asserted-by":"publisher","first-page":"2663","DOI":"10.1016\/S0140-6736(24)01299-6","article-title":"Lung cancer treatment:\n20 years of progress","volume":"403","author":"The\nLancet","year":"2024","journal-title":"Lancet"},{"issue":"7","key":"2026081812114963700_cit2","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1056\/NEJMoa1916623","article-title":"The Effect\nof Advances in Lung-Cancer Treatment on Population Mortality","volume":"383","author":"Howlader","year":"2020","journal-title":"N. Engl. J. Med."},{"issue":"3","key":"2026081812114963700_cit3","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics\n2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for\n36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"Ca-Cancer J. Clin."},{"issue":"4 Suppl 6","key":"2026081812114963700_cit4","first-page":"10","article-title":"The expanding\nrole of cisplatin in the treatment of\nnon-small-cell lung cancer","volume":"16","author":"Bunn","year":"1989","journal-title":"Semin. Oncol."},{"issue":"4","key":"2026081812114963700_cit5","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1177\/10781552241234847","article-title":"Successful switch to\ncisplatin-based chemotherapy in a patient with lung cancer who developed\na carboplatin-induced hypersensitivity reaction","volume":"30","author":"Nagata","year":"2024","journal-title":"J. Oncol. Pharm. 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Chem."},{"issue":"19","key":"2026081812114963700_cit34","doi-asserted-by":"publisher","first-page":"2437","DOI":"10.1038\/sj.onc.1202189","article-title":"Interaction with cyclin-dependent\nkinases and PCNA\nmodulates proteasome-dependent degradation of p21","volume":"17","author":"Cayrol","year":"1998","journal-title":"Oncogene"},{"issue":"22","key":"2026081812114963700_cit35","first-page":"5187","article-title":"p21 is necessary for the p53-mediated\nG1 arrest in human cancer cells","volume":"55","author":"Waldman","year":"1995","journal-title":"Cancer Res."},{"issue":"1","key":"2026081812114963700_cit36","doi-asserted-by":"publisher","first-page":"15410","DOI":"10.1038\/s41598-020-72420-w","article-title":"Ruthenium (II) complex cis-[Ru\u00ad(II)\u00ad(n(2)-O(2)\u00adCC(7)\u00adH(7)\u00adO(2))\u00ad(dppm)(2)]\u00adPF(6)-hmxbato\ninduces ROS-mediated apoptosis in lung tumor cells producing selective\ncytotoxicity","volume":"10","author":"Costa","year":"2020","journal-title":"Sci. Rep."},{"key":"2026081812114963700_cit37","doi-asserted-by":"publisher","first-page":"104679","DOI":"10.1016\/j.tiv.2019.104679","article-title":"Ruthenium (II)\ncomplexes with N, O-chelating proline and threonine ligands cause\nselective cytotoxicity by the induction of genomic instability, cell\ncycle arrest and apoptosis in breast and prostate tumor cells","volume":"62","author":"de\nSousa","year":"2020","journal-title":"Toxicol. In Vitro"},{"key":"2026081812114963700_cit38","doi-asserted-by":"publisher","first-page":"112022","DOI":"10.1016\/j.jinorgbio.2022.112022","article-title":"Synthesis,\ncharacterization and in\nvitro cytotoxicity of ruthenium\u00ad(II) metronidazole complexes: Cell\ncycle arrest at G1\/S transition and apoptosis induction in MCF-7 cells","volume":"237","author":"Candido","year":"2022","journal-title":"J. Inorg. Biochem."},{"issue":"68","key":"2026081812114963700_cit39","doi-asserted-by":"publisher","first-page":"63143","DOI":"10.1039\/C6RA11391E","article-title":"Apoptosis, autophagy, cell cycle arrest, cell invasion\nand BSA-binding studies in vitro of ruthenium\u00ad(ii) polypyridyl complexes","volume":"6","author":"Lai","year":"2016","journal-title":"RSC Adv."},{"issue":"6","key":"2026081812114963700_cit40","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202201159","article-title":"Paradoxical roles of caspase-3 in regulating cell survival,\nproliferation, and tumorigenesis","volume":"221","author":"Eskandari","year":"2022","journal-title":"J. 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