Evaluation of newly synthesized schiff base Pd(II) complexes for prostate cancer treatment through in vitro cytotoxicity and molecular mechanistic studies
Damnjan Pantic, Nikola Mirković, Tatjana Vulović, Danijela Jovanović, Stefan Jakovljević, Petar Čanović, Milan Zarić, Radica Živković Zarić, Marina D. Kostić, Jovana S. Dragojević, Vera M. Divac, Žiko Milanović, Kristina Milisavljevic, Marina Mitrović, Ivanka Zelen
Abstract
Introduction Palladium (II) complexes are promising anticancer agents with potential advantages over platinum drugs. This study aimed to synthesize and characterize three new Pd(II) complexes ( 2a–2c ) with Schiff base ligands derived from salicylic acid and amine scaffolds, and to evaluate their antitumor activity against prostate cancer cells. Methods The Pd(II) complexes were synthesized and structurally characterized. Cytotoxicity was tested on two human prostate cancer cell lines (PC-3, DU-145) and healthy fibroblasts (MRC-5). Apoptosis induction was assessed by flow cytometry, with a focus on Bcl-2 and caspase proteins. Molecular docking was used to examine binding to the androgen receptor (AR) and apoptotic regulators (CASP3, BCL2, BAX). DNA and human serum albumin (HSA) binding were also investigated. Results All complexes showed significant cytotoxicity. Notably, complex 2c exhibited more potent cytotoxic activity than cisplatin in prostate cancer cell lines, with lower IC 50 values after 72 h exposure in DU-145 (7.1 µM vs. 8.2 µM) and PC-3 cells (8.6 µM vs. 21.9 µM), while showing reduced toxicity in normal MRC-5 cells (42.3 µM vs. 24.4 µM). Apoptosis was confirmed as the primary cytotoxic mechanism, involving the activation of Bcl-2 and caspases. Docking studies revealed that complex 2c had the strongest binding affinity to AR and apoptotic proteins, mediated by hydrogen bonds, π–π stacking, and hydrophobic interactions. DNA and HSA binding supported their biological relevance. Conclusion Complex 2c exhibits potent anticancer activity through the induction of apoptosis and dual targeting of the AR and apoptotic pathways, making it a promising candidate for further development of anticancer drugs.