Cellular and biomolecular responses of human ovarian cancer cells to cytostatic dinuclear platinum(II) complexes

Abstract

Polynuclear platinum(II) complexes represent a class of potential anticancer agents that have shown promising pharmacological properties in preclinical studies. The nature of cellular responses induced by these complexes, however, is poorly understood. In this research, the cellular responses of human ovarian cancer COC1 cells to dinuclear platinum(II) complexes {[cis-Pt(NH₃)₂Cl]₂L¹}(NO₃)₂ (1) and {[cis-Pt(NH₃)₂Cl]₂L²}(NO₃)₂ (2) (L¹ = α,α'-diamino-p-xylene, L² = 4,4'-methylenedianiline) has been studied using cisplatin as a reference. The effect of platinum complexes on the proliferation, death mode, mitochondrial membrane potential, and cell cycle progression has been examined by MTT assay and flow cytometry. The activation of cell cycle checkpoint kinases (CHK1/2), extracellular signal-regulated kinases (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) of the cells by the complexes has also been analyzed using phospho-specific flow cytometry. Complex 1 is more cytotoxic than complex 2 and cisplatin at most concentrations; complex 2 and cisplatin are comparably cytotoxic. These complexes kill the cells through an apoptotic or apoptosis-like pathway characterized by exposure of phosphatidylserine and dissipation of mitochondrial membrane potential. Complex 1 shows the strongest inductive effect on the morphological changes of the cells, followed by cisplatin and complex 2. Complexes 1 and 2 arrest the cell cycle in G2 or M phase, while cisplatin arrests the cell cycle in S phase. The influence of these complexes on CHK1/2, ERK1/2, and p38 MAPK varies with the dose of the drugs or reaction time. Activation of phospho-ERK1/2 and phospho-p38 MAPK by these complexes is closely related to the cytostatic activity. The results demonstrate that dinuclear platinum(II) complexes can induce some cellular responses different from those caused by cisplatin.

Noble metals in medicine: Latest advances

“…Furthermore, when a macromolecular crowding agent is added to mimic the environmental conditions in the cell nucleus, the Pt 3 species crosslinks two DNA duplexes with a high yield, where this feature was observed for the first time in antitumor trinuclear platinum complexes [25]. Other dinuclear complexes with aromatic diamines and picoline derivatives have been tested against ovarian and breast cancers, where they yielded comparable or higher cytotoxicity than cisplatin, but the induced cellular responses differed from those caused by the lead drug [26,27].…”

Noncovalent Interactions between a Trinuclear Monofunctional Platinum Complex and Human Serum Albumin

“…The distance between HSA and complex 1 is less than 7 nm, indicating that a static quenching interaction has occurred. 23 Further, the fluorescence quenching mechanism can be described by the Stern−Volmer equation: 24 (4) where K sv is the Stern−Volmer constant, [Q] is the concentration of complex 1, K q is the quenching rate constant of HSA, and τ 0 is the lifetime of HSA without complex 1, respectively. Obviously, (5) The Stern−Volmer plots of HSA in the presence of complex 1 at different concentrations and temperatures are shown in Figure 9.…”

Cell death-inducing effect of novel palladium(II) and platinum(II) complexes on non-small cell lung cancer cells in vitro

“…Platinum(II) (Pt) complexes including cisplatin and its derivatives have been widely recognized as potent anticancer agents, eVective against diVerent types of cancer in vitro (Lin et al 2011;Neves et al 2010). After the discovery of its activity, thousands of platinum complexes have been synthesized and tested so far.…”