Synthesis, characterization and investigation of the mode of action in the anticancer activity of novel platinum complexes
Date
2024
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of the Witwatersrand, Johannesburg
Abstract
Cancer remains a global health concern, causing approximately 10 million deaths in 2020. Lung cancer, accounting for 18% of cancer-related deaths, and colorectal
cancer, contributing 9.4%, are major contributors to this alarming statistic, emphasizing the urgent need for innovative and effective treatment options. Despite
the success of platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin, their limitations and severe adverse effects necessitate the exploration of alternative chemotherapeutic agents. This research project focused on synthesizing and characterizing square planar platinum(II) complexes bearing variations of two bidentate coordinating ligands; disubstituted acylthiourea and diimine ligands, each possessing unique physical and chemical properties.
A series of cationic [Pt(diimine)(Ln-κO,S)]Cl complexes were successfully synthesized and characterized using nuclear magnetic resonance spectroscopy, infrared spectroscopy, mass spectrometry, and elemental analysis. The anticancer activity of these complexes was evaluated against two lung cancer cell lines, A549
and H1975, and a colorectal cancer cell line, HT-29. In vitro cytotoxicity studies included the determination of IC50 values of active complexes and assessing their
cell death mechanisms through multiple biochemical marker assays. These included annexin-V binding, caspase-3/7 and caspase-8 activity, mitochondrial membrane
potential (MMP), reactive oxygen species (ROS) and immunofluorescence for the expression of key proteins involved in the DNA damage response and oxidative
stress response, such as p21 and haemoxygenase-1 (HO-1). A proteome array was employed to investigate the effects on apoptosis-associated proteins. The results indicated that these platinum complexes were more cytotoxic than cisplatin with IC50 values ranging between 0.68 μM and 2.28 μM. Further investigation showed that the platinum complexes induced cell stress, chromatin condensation, nuclear fragmentation, increased phosphatidylserine (PS) on the outer cell membranes and activated caspase-3/7. Platinum complexes induced intrinsic apoptosis in cancer cells, as evidenced by the loss of mitochondrial membrane potential and the absence of caspase-8 activity. Elevated ROS levels, increased HO-1 expression and increased expression of p21 suggested oxidative stress and DNA damage as the trigger source for intrinsic apoptotic cell death. The active complexes downregulated pro-survival proteins (IGFs) in lung cancer cells and anti-apoptotic proteins (survivin and HSP70) and upregulated pro-apoptotic proteins (p21, TRAIL R2), across the three cancer cell lines, indicating potential dual activation of apoptotic pathways. DNA binding studies indicated groove binding and intercalation as the mode of interaction with DNA. The findings highlight the potential of these platinum complexes as promising candidates for further development as cancer therapeutics.
Description
A thesis submitted in fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry to the Faculty of Science, University of the Witwatersrand, Johannesburg, South Africa 2024
Keywords
Cancer, Synthesis, Characterization, Disubstituted acylthiourea, Diimine, Platinum(II) complexes, Bidentate coordination, Apoptosis, Oxidative stress, UCTD, Groove binding, Intercalation
Citation
Peega, Tebogo. (2024). Synthesis, characterization and investigation of the mode of action in the anticancer activity of novel platinum complexes [PhD thesis, University of the Witwatersrand, Johannesburg]. WireDSpace.