title: A novel PI3K axis selective molecule exhibits potent tumor inhibition in colorectal carcinogenesis.
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 G1arrest 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.
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Aashiq
authors.initials: A
authors.lastname: Hussain
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Asif Khurshid
authors.initials: AK
authors.lastname: Qazi
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Nagaraju
authors.initials: N
authors.lastname: Mupparapu
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Mubashir Javeed
authors.initials: MJ
authors.lastname: Mintoo
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Girish
authors.initials: G
authors.lastname: Mahajan
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.
authors.forename: Parduman Raj
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.|CSIR-Academy of Scientific and Innovative Research, Govt. of India.
authors.forename: Shashank Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.|CSIR-Academy of Scientific and Innovative Research, Govt. of India.
authors.forename: Sandip B
authors.initials: SB
authors.lastname: Bharate
authors.affiliation: Department of Biochemistry, University of Kashmir, Srinagar, India.
authors.forename: Mohmmad Afzal
authors.initials: MA
authors.lastname: Zargar
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.|CSIR-Academy of Scientific and Innovative Research, Govt. of India.
authors.forename: Qazi Naveed
authors.initials: QN
authors.lastname: Ahmed
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.|CSIR-Academy of Scientific and Innovative Research, Govt. of India.
authors.forename: Dilip Manikrao
authors.initials: DM
authors.lastname: Mondhe
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.|CSIR-Academy of Scientific and Innovative Research, Govt. of India.
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, India.|CSIR-Academy of Scientific and Innovative Research, Govt. of India.
authors.forename: Abid
authors.initials: A
authors.lastname: Hamid
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D012007:Rectum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D052999:Quinazolinones; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: PI3K; colorectal cancer; inhibitor; signaling; therapeutics