title: A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT-116 cells.
abstract: We have synthesized a novel quinazolinone chalcone derivative (QC) and first time reported its in-vitro and in-vivo anticancer potential. It inhibited the cell proliferation of different cancer cell lines like PC-3, Panc-1, Mia-Paca-2, A549, MCF-7 and HCT-116. It induces apoptosis as measured by several biological endpoints such as apoptotic body formation, evident by Hoechst and scanning electron microscopy, enhanced annexinV-FITC binding of the cells, increased sub-G0 cell fraction, loss of mitochondrial membrane potential (Δψm), reduction of Bcl-2/Bax ratio, activation of caspase-9, caspase-3 and PARP-1 (poly-ADP Ribose polymerase) cleavage in HCT-116 cells. In spite of apoptosis, QC significantly hammers the downstream and upstream signaling cascade of PI3K/Akt/mTOR pathway and cell cycle regulator Skp-2, p21 and p27. Interestingly, QC induces the S and G2/M phase of HCT-116 cells at experimental doses. QC inhibits the tumor growth of Ehrlich ascites carcinoma (EAC), Ehrlich tumor (ET, solid) and sarcoma-180(solid) mice models. Furthermore, it was found to be non-toxic as no animal mortality (0/7) occurred during experimental doses. The present study provides an insight of anticancer potential of QC, which may be useful in managing and treating cancer.
authors.affiliation: Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Zahoor Ahmad
authors.initials: ZA
authors.lastname: Wani
authors.affiliation: Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Guru
authors.affiliation: Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500607, India.
authors.forename: A V Subba
authors.initials: AV
authors.lastname: Rao
authors.affiliation: Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Sonia
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Girish
authors.initials: G
authors.lastname: Mahajan
authors.affiliation: Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Behl
authors.affiliation: Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India.
authors.forename: P R
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500607, India.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.affiliation: Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India. Electronic address: sbhushan@iiim.ac.in.
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.affiliation: Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu, 180001, India. Electronic address: dmmondhe@iiim.ac.in.
authors.forename: Dilip M
authors.initials: DM
authors.lastname: Mondhe
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D047188:Chalcones; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D052999:Quinazolinones; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: Apoptosis; PI3K/Akt/mTOR; Quinazolinone-chalcone; Sarcoma-180