A novel PI3K axis selective molecule exhibits potent tumor inhibition in colorectal carcinogenesis
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...
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Published in | Molecular carcinogenesis Vol. 55; no. 12; pp. 2135 - 2155 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Blackwell Publishing Ltd
01.12.2016
Wiley Subscription Services, Inc |
Subjects | |
Online Access | Get full text |
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Summary: | 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 that the PI3K‐Akt signaling regulated apoptosis and autophagy through different mechanisms but mTORC1 mediated autophagy appeared not to be involved in the cell death induction by DHNQ. The molecule also showed significant anticancer efficacy in in vivo tumor models without any mortality indicating its non‐toxic nature with possible clinical significance. Overall, the selective elucidation of DHNQ molecular mechanism will provide the possible strategies for the clinical development in CRC that may respond to this specific, potent and novel P13K inhibitor. © 2016 Wiley Periodicals, Inc. |
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Bibliography: | ark:/67375/WNG-MPNLBG4X-K istex:0762AEE0088F498272129B937292F69D6FB7EF12 ArticleID:MC22457 CSIR grant - No. BSC-0205 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0899-1987 1098-2744 |
DOI: | 10.1002/mc.22457 |