{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:40:47Z","timestamp":1760060447708,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality, with resistance to chemotherapy representing a major therapeutic challenge. In this study, we investigated the effects of conventional chemotherapeutics, Cisplatin and 5-fluorouracil (5-FU), in combination with small molecule inhibitors (SMIs) targeting the PI3K\/AKT signaling pathway, on NSCLC cell viability. Two NSCLC cell lines, H460 (large cell lung carcinoma) and A549 (adenocarcinoma), both characterized by constitutive activation of PI3K\/AKT signaling, were evaluated. A normal human lung fibroblast cell line, MRC-5, was used as a non-cancer control to assess selectivity and exclude cytotoxic effects. Dose\u2013response analyses were performed to determine the optimal concentrations of Cisplatin, 5-FU, the AKT inhibitor MK2206, and the PI3K inhibitor BKM120, both as monotherapies and in combination treatments. We identified a synergistic combination of 5-FU and BKM120 that significantly reduced viability and induced apoptosis in NSCLC cells while sparing MRC-5 cells. Mechanistic studies revealed that apoptosis induction was mediated through the apoptotic pathway regulated by the Bcl-2 family and activation of caspase-3 and caspase-6. These findings highlight the therapeutic potential of combining PI3K\/AKT inhibitors with conventional chemotherapy to overcome resistance mechanisms in NSCLC.<\/jats:p>","DOI":"10.3390\/ijms26178378","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T08:01:01Z","timestamp":1756454461000},"page":"8378","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing Chemotherapeutic Efficacy in Lung Cancer Cells Through Synergistic Targeting of the PI3K\/AKT Pathway with Small Molecule Inhibitors"],"prefix":"10.3390","volume":"26","author":[{"given":"Maria","family":"Michael","sequence":"first","affiliation":[{"name":"Apoptosis and Cancer Chemoresistance Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University of Cyprus, Nicosia 2404, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Christou","sequence":"additional","affiliation":[{"name":"Tumor Microenvironment, Metastasis and Experimental Therapeutics Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0730-6876","authenticated-orcid":false,"given":"Iason","family":"Kanakas","sequence":"additional","affiliation":[{"name":"Apoptosis and Cancer Chemoresistance Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University of Cyprus, Nicosia 2404, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0823-2888","authenticated-orcid":false,"given":"Christiana M.","family":"Neophytou","sequence":"additional","affiliation":[{"name":"Apoptosis and Cancer Chemoresistance Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University of Cyprus, Nicosia 2404, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. 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