Novel Platinum II and Platinum IV complexes exhibit potent antineoplastic activity against breast cancer in vitro and in vivo

Abstract

The success of platinum-based chemotherapy in treating several types of cancers came along with the burden of resistance and severe side effects. Scientists, therefore, were prompted to search for analogs that have greater effectiveness and fewer adverse effects. Previous studies on 5CLSS(II) and 5CLSS(IV) showed that these complexes had high cytotoxic activity against lung cancer cells. The current study focuses on investigating the chemotherapeutic potential of the two complexes along with a third platinum IV analog on breast cancer both in vitro and in vivo. Cytotoxicity of the three complexes was determined using the viability assay (WST-1 assay) on invasive metastatic breast cancer cells (MDA-MB-231) 72 hours post-treatment. Cellular uptake and intracellular accumulation of the complexes was determined using inductively coupled plasma mass spectrometry (ICP-MS). Mode of cell death was assessed using flow cytometry. All three complexes exhibited high cytotoxicity against MDA-MB-231 cells, with IC50 of 0.447, 0.922, and 1.94 μM for 5CLSS(II), 5CLSS(IV), and P-BUT respectively. The complexes were also shown to be actively transported into MDA-MB-231 cells and largely accumulating in the nuclear/cytoskeletal fraction. These complexes induced cell death via apoptosis as revealed using flow cytometry. A dose escalation and toxicity studies were conducted on adult female Sprague Dawley rats to determine the most tolerated dose and toxicity of the complexes respectively. The chemotherapeutic effect of the three complexes (IP treatment; 4 weeks) was evaluated in a chemically-induced (DMBA) breast cancer model in rats. The dose escalation study revealed that the most tolerated dose for 5CLSS(II), 5CLSS(IV), and P-BUT were 50, 75 and 75 mg/kg body weight respectively. The 28-day toxicity study showed that incremental doses up to 15 mg/kg for 5CLSS(II), and 30 mg/kg for 5CLSS(IV) and P-BUT did not cause any death or adverse effect on both liver and kidney function. 5CLSS(II) and 5CLSS(IV) at doses of 1 and 5 mg/kg body weight, and P-BUT at 15 mg/kg body weight reduced tumor weight by 93 to 100% compared to control while showing no signs of toxicity. In conclusion, the current study shows that 5CLSS(II), 5CLSS(IV), and P-BUT possess potent antineoplastic activity against breast cancer both in vitro and in vivo with relatively low toxicity and therefore could be considered as alternatives to currently used platinum-based chemotherapeutic drugs.