Abstract
BackgroundColorectal cancer (CRC) is a heterogeneous tumor having various genetic alterations. The current treatment options had limited impact on disease free survival due to therapeutic resistance. Novel anticancer agents are needed to treat CRC specifically metastatic colorectal cancer. A novel coordination complex of platinum, (salicylaldiminato)Pt(II) complex with dimethylpropylene linkage (PT) exhibited potential anti-cancer activity. In this study, we explored the molecular mechanism of PT-induced cell death in colorectal cancer.MethodsColony formation was evaluated using the clonogenic assay. Apoptosis, cell cycle analysis, reactive oxygen species, mitochondrial membrane potential and caspase-3/− 7 were assessed by flow cytometry. Glutathione level was detected by colorimetric assay. PT-induced alteration in pro-apoptotic/ anti-apoptotic proteins and other signaling pathways were investigated using western blotting. P38 downregulation was performed using siRNA.ResultsIn the present study, we explored the molecular mechanism of PT-mediated inhibition of cell proliferation in colorectal cancer cells. PT significantly inhibited the colony formation in human colorectal cancer cell lines (HT-29, SW480 and SW620) by inducing apoptosis and necrosis. This platinum complex was shown to significantly increase the reactive oxygen species (ROS) generation, depletion of glutathione and reduced mitochondrial membrane potential in colorectal cancer cells. Exposure to PT resulted in the downregulation of anti-apoptotic proteins (Bcl2, BclxL, XIAP) and alteration in Cyclins expression. Furthermore, PT increased cytochrome c release into cytosol and enhanced PARP cleavage leading to activation of intrinsic apoptotic pathway. Moreover, pre-treatment with ROS scavenger N-acetylcysteine (NAC) attenuated apoptosis suggesting that PT-induced apoptosis was driven by oxidative stress. Additionally, we show that PT-induced apoptosis was mediated by activating p38 MAPK and inhibiting AKT pathways. This was demonstrated by using chemical inhibitor and siRNA against p38 kinase which blocked the cytochrome c release and apoptosis in colorectal cancer cells.ConclusionCollectively, our data demonstrates that the platinum complex (PT) exerts its anti-proliferative effect on CRC by ROS-mediated apoptosis and activating p38 MAPK pathway. Thus, our findings reveal a novel mechanism of action for PT on colorectal cancer cells and may have therapeutic implication.
Highlights
Colorectal cancer (CRC) is a heterogeneous tumor having various genetic alterations
To explore the anticancer activity of platinum complex (PT), we tested the effect of PT at 5 and 10 μM on in-vitro tumorigenicity of HT-29, SW480 and SW620 cells
These results demonstrate that this platinum complex has antitumorigenic activity in human colorectal cancer cell lines
Summary
Colorectal cancer (CRC) is a heterogeneous tumor having various genetic alterations. Novel anticancer agents are needed to treat CRC metastatic colorectal cancer. We explored the molecular mechanism of PT-induced cell death in colorectal cancer. 1.8 million new CRC cases are diagnosed annually [2]. The development of colorectal cancer involves three major routes, adenoma to carcinoma, inflammatory pathway and serrated pathway [1]. Most of colorectal cancers are adeno-carcinoma that arises from glandular intestinal epithelial cells of the colorectum [3]. Colorectal cancer constitutes an aetiologically heterogeneous disease categorized by tumor location and global gene alterations [4]. 60% of colorectal cancer cases develop sporadically without a family history of CRC along with increased CRC risk by inheriting genetic mutations [5]. The increased incidence of CRC in younger population is an emerging trend [7]
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