Computational and in vitro characterization of ICY‐5: A potential candidate promoting mitochondrial apoptosis via the c‐MET and STAT3 pathways

Abstract

Targeted chemotherapy remains the primary choice in controlling various forms of breast cancer (BC) due to its heterogenous gene expressions in various subtypes. In silico and in vitro evaluation of ICY-5, a novel arylidene analogue against c-MET, was performed. ICY-5 exhibited a docking score of −9.6 kcal/mol in inactive conformation and, − 8.6 kcal/mol in active conformation for c-MET. ICY-5 inhibited c-MET enzyme with an IC 50 of 34.34 nM. The compound effectively inhibited MDA-MB 231 and MCF-7 cell proliferation, with GI 50 values of 62.61 and 75.31 nM, respectively, and hepatocyte growth factor (HGF)/R c-MET phosphorylation with IC 50 s of 71.41 and 83.77 nM, respectively. ICY-5 dose-dependently inhibited HGF-induced transmigration, cell scattering, invasion and altered cell cycle. An increase in apoptotic populations of these cells, with a dose-dependent decease in phosphorylation of STAT3 protein was observed. Furthermore, ICY-5 upregulated the caspase-3, caspase-9, Bcl-2-associated X and survivin, and downregulated Bcl-2, vascular endothelial growth factor, matrix metalloproteinase-2 (MMP-2), and MMP-9 in both BC cell lines. In summary, ICY-5 exhibited excellent efficacy in BC cells, targeting c-MET/SAT-3-mediated mitochondrial apoptosis. Further research will be required to ascertain ICY-5 suitability as a targeted chemotherapeutic against multiple forms of BC.

SSB-2548 Attenuates C-X-C chemokine receptor type 4 (CXCR-4) Activation to Induce Apoptosis; An in silico Guided invitro Validation in Acute Myeloid Leukemia cells

“…All three AML cells were treated with different doses of SSB-2548 along with DMSO controls and incubation for 48 h. Apoptosis was analyzed by using Annexin V detection kit as described elsewhere [22]. Percentage of early and late phase apoptotic populations in comparison to respective controls were presented.…”

Neferine induces apoptosis by modulating the ROS‑mediated JNK pathway in esophageal squamous cell carcinoma

“…Apoptosis refers to the active and orderly death of cells that maintains homeostasis of the internal environment under physiological or pathological conditions ( 17 , 18 ). Exposure of cells to internal pro-apoptotic factors, such as activators of oncogenes, agents that cause DNA damage, cell hypoxia, and deficiency of cell growth factors, has been revealed to activate apoptosis of mitochondrial cells ( 19 ). Previous studies have demonstrated that dysregulation of apoptosis can result in a variety of human diseases, including development and regression of tumors ( 20 , 21 ).…”