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Computational and in vitro characterization of ICY‐5: A potential candidate promoting mitochondrial apoptosis via the c‐MET and STAT3 pathways
Author(s) -
Al Shahrani Mesfer,
Balasubramaniam Meenakshisundaram,
Alshahrani Mohammad Y.,
Saif Ahmed,
Dera Ayed A.,
Alasmari Sultan,
Abohassan Mohammad,
Makkawi Mohammed,
Radhakrishnan Suresh,
Rajagopalan Prasanna
Publication year - 2021
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29830
Subject(s) - apoptosis , survivin , hepatocyte growth factor , in vitro , cell culture , chemistry , caspase 3 , phosphorylation , microbiology and biotechnology , cancer research , programmed cell death , biology , biochemistry , genetics , receptor
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.