Cell Signal. 2020 Oct 3:109803. doi: 10.1016/j.cellsig.2020.109803. Online ahead of print.
Recent global incidences and mortality rates have placed colorectal cancer (CRC) at third and second positions, respectively, among both sexes of all ages. Resistance during chemotherapy is a big problem in the treatment and disease-free survival of CRC patients. Discovery of new anticancer drug(s) is a time taking process and therefore, invites studies for repurposing the known therapeutics. The present study was conceived to analyze the anticancer role of Imatinib in experimental CRC at early
stages. Different experimental procedures e.g. tumor incidences or histoarchitectural changes, gene and protein expression analysis, estimations of intracellular calcium, ROS, mitochondrial membrane potential, apoptotic index and molecular docking was performed to support the hypothesis. It was observed that Imatinib could function as an immunomodulator by breaking the feed-back loop between the proinflammatory cytokines (IL-1β and TNF-α) and transcription factors (NF-κB, Jak3/Stat3) knowingly involved in increased cell proliferation during tumorigenesis via activating different intracellular signaling. Also, Imatinib could independently deregulate the other cell survival and proliferation signaling e.g. PI3-K/Akt/mTOR, Wnt/β-catenin and MAPK. Proinflammatory cytokines orchestrated intracellular signaling also involve angiogenic factors to be upregulated during CRC which were also seemed to be independently suppressed by Imatinib. Restoration of physiological apoptosis by increasing the release of intracellular calcium to generate ROS thereby reducing the mitochondrial membrane potential for the release of cytochrome c and activation of caspase-3 was also reported with Imatinib administration. Thus, it may be suggested that Imatinib show synergistic pleiotropy in suppressing the interlinked tumorigenic signaling pathways independently.