Accepted Manuscript (unedited) The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 1 | Page Cytotoxicity induced by newly synthesized palladium(II) complexes lead to the death of MCF-7 and MDA-MB-435 cancer cell lines Bruna Alexandre Oliveira da Silva 1* , Isabela Spido Dias 1 , Luís Eduardo Sarto 2 , Elba Pereira de Gois 3 , Claúdia Torres 3 , Eduardo Tonon de Almeida 3 , Cibele Marli Cação PaivaGouvêa 1 1 Institute of Natural Sciences, Federal University of Alfenas, Alfenas, Brazil; 2 Federal Institute of Education, Science and Technology of the South of Minas Gerais, Machado, Brazil; 3 Institute of Chemistry, Federal University of Alfenas, Alfenas, Brazil. Running title: Palladium(II) complexes cytotoxicityon cancer cells *Correspondingauthor: Bruna Alexandre Oliveira da Silva, Tel: +55 35 37019690, e-mail: bruna.silva@unifal-mg.edu.br. Abstract Purpose: Breast cancer is the most common female malignancy and melanoma is the most lethal type of skin cancer. Traditional therapy for cancer treatment is far from satisfactory due to drug resistance and side effects, thus a search for new medicines is being emphasized. Palladium(II) complexes have been reported as anticancer potential agents. In this work, the anticancer activities and cell death induction of a new series of square-planar palladium(II) complexes were evaluated against MCF-7 and MDA-MB-435 cancer cells. Methods: MCF-7 (breast carcinoma) and MDA-MB-435 (melanoma) cells were cultivated, and treated with ligand and Pd(II) complexes. Cell growth, migration and adhesion inhibition, morphological alterations, cell death induction and, DNA interaction upon treatment were studied. Results: Pd(II) complexes exhibited both short and long-term antiproliferative effects on both cell lines, reducing by 80% cell growth in the SRB assay and abolishing long-term proliferation, estimated by the clonogenic assay. Complexes reduced significantly (p < 0.05) cell migration and adhesion when compared to the control group. Complexes induced morphological alterations in cell lines and significant (p<0.05) cellular shrinkage. Cell death was induced and the complexes were able to interact with DNA, inducing cleavage of double- stranded DNA, which may account for the complexes cytotoxic effects, observed against both MCF-7 and MDA-MB-435 cells. Conclusion: Overall, the complexes exhibited cytotoxic activities and induced cell death. These observations emphasize an anticancer role with a potential therapeutic value for Pd(II) complexes to improve the outcome of patients with breast cancer and melanoma. How to cite this article: Silva BAO, Dias LS, Sarto LE, Gois EP, Torres C, Almeida ET, PaivaGouvêa CMC. Cytotoxicity induced by newly synthesized palladium(II) complexes lead to the death of MCF-7 and MDA-MB-435 cancer cell lines. Advanced Pharmaceutical Bulletin, doi: 10.34172/apb.2023.017 Accepted Manuscript