A novel PI3K axis selective molecule exhibits potent tumor inhibition in colorectal carcinogenesis

Molecular Carcinogenesis
Aashiq HussainAbid Hamid

Abstract

Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is responsible for initiation, chemo-resistance, and poor prognosis of colorectal cancer (CRC). Therefore, PI3K pathway inhibition can provide a plausible way of attaining CRC treatment. We report PI3K target specific synthesis and selection of a potent molecule, that is, 2,3-dihydro-2-(naphthalene-1-yl) quinazolin-4(1H)-one (DHNQ) from quinazolinone series based on the structural activity relationship after evaluation in diverse cancers. This molecule inhibited the PI3K enzyme activity and transcriptional as well as translational expression levels in colorectal cancer (CRC) models. This was associated with subsequent decrease in phosphorylation of its downstream effector proteins, that is, p-Akt(Ser-473) and p-mTORC1(Ser-2448) and decreased ERK signaling. Furthermore, DHNQ decreased expression of cyclins that caused G1 arrest and decreased Bcl-2/Bax ratio after mitochondrial membrane potential loss, reactive oxygen species generation, and an increase in cytosolic Ca2+ loads that is responsible for the decreased CRC cell proliferation and survival. These biochemical changes triggered apoptotic cell death with altered autophagic Beclin-1 and LC3β expression. It seemed tha...Continue Reading

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