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To enhance photodynamic therapeutic effects in vitro, the present study was designed to reduce dose-dependence in photodynamic therapy (PDT) and evaluate the anticancer effects of Dicoma anomala (D. anomala) root extracts (i.e., chloroform (Chl), ethyl acetate (EtOAc), and methanol (MeOH)) on A549 lung cancer cells. The most active extract of D. anomala (D.A) was used to establish the 50% inhibitory concentration (IC50), which was further used to evaluate the anticancer efficacy of D.A in combination with ZnPcS4-mediated PDT IC50. The study further evaluated cell death mechanisms by cell viability\/ cytotoxicity (LIVE\/DEADTM assay), flow cytometry (Annexin V-fluorescein isothiocyanate (FITC)-propidium iodide (PI) staining), immunofluorescence (p38, p53, Bax, and caspase 3 expressions), and fluorometric multiplex assay (caspase 8 and 9) 24 h post-treatment with IC50 concentrations of ZnPcS4-mediated PDT and D.A MeOH root extract. Morphological changes were accompanied by a dose-dependent increase in cytotoxicity, decrease in viability, and proliferation in all experimental models. Apoptosis is the highly favored cell death mechanism observed in combination therapy groups. Apoptotic activities were supported by an increase in the number of dead cells in the LIVE\/DEADTM assay, and the upregulation of p38, p53, Bax, caspase 3, 8, and 9 apoptotic proteins. In vitro experiments confirmed the cytotoxic and antiproliferative effects of D.A root extracts in monotherapy and in combination with ZnPcS4-mediated PDT. Taken together, our findings demonstrated that D.A could be a promising therapeutic candidate worth exploring in different types of cancer.<\/jats:p>","DOI":"10.3390\/cells11203288","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T20:32:23Z","timestamp":1666211543000},"page":"3288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["In Vitro Cell Death Mechanisms Induced by Dicoma anomala Root Extract in Combination with ZnPcS4 Mediated-Photodynamic Therapy in A549 Lung Cancer Cells"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8129-700X","authenticated-orcid":false,"given":"Alexander","family":"Chota","sequence":"first","affiliation":[{"name":"Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 1711, Doornfontein 2028, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7062-4412","authenticated-orcid":false,"given":"Blassan P.","family":"George","sequence":"additional","affiliation":[{"name":"Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 1711, Doornfontein 2028, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5002-827X","authenticated-orcid":false,"given":"Heidi","family":"Abrahamse","sequence":"additional","affiliation":[{"name":"Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 1711, Doornfontein 2028, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kerr, D.J., Haller, D.G., van de Velde, C.J.H., and Baumann, M. 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