title: Quinazoline based small molecule exerts potent tumour suppressive properties by inhibiting PI3K/Akt/FoxO3a signalling in experimental colon cancer.
abstract: Deregulation of PI3K signalling pathway is strongly involved in pathology of cancer and development of resistance in tumour cells. Here, we report that pharmacologically active vasicinone analogue, RLX (7, 8, 9, 10-Tetrahydroazepino [2, 1-b] quinazolin-12-(6H)-on), exhibited potent anticancer activities both in vitro and in vivo. In this study, RLX treatment displayed strong inhibition of proliferation against various cancer cell lines. However, colon cancer cells were found to be the most sensitive towards RLX mediated inhibition of proliferation. The result showed that RLX treatment followed strong concentration dependent inhibition of HCT-116 cell proliferation and colony formation. RLX treatment to HCT-116 was observed to be associated with down-regulation of p110α and p85 subunits of PI3K thereby decreasing the expression of subsequent downstream effector proteins. Interestingly, silencing of PI3K gene by siRNA in combination with RLX confirmed the anti-proliferation effect of RLX against HCT-116 cells and is mediated by the PI3K pathway. We also found that RLX induced sub-G1 arrest and mitochondrial potential loss followed by pFoxO3a(Thr32) nuclear-cytoplasmic translocation inhibition. Moreover, RLX treatment in in vivo models substantially resulted in a tumour growth inhibition. Overall, our findings reveal the functional role of the PI3K/Akt/FoxO3a pathway that gets deregulated in cancer and suggests its simultaneous targeting by RLX thereby further identifying the compound as a potent inhibitor of the PI3K/Akt/FoxO3a pathway under in vitro and tumour regression in vivo.
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
authors.forename: Asif Khurshid
authors.initials: AK
authors.lastname: Qazi
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
authors.forename: Aashiq
authors.initials: A
authors.lastname: Hussain
authors.affiliation: Plant Biotechnology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
authors.forename: Saima
authors.initials: S
authors.lastname: Khan
authors.affiliation: Natural Product Microbes Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
authors.forename: Mushtaq A
authors.initials: MA
authors.lastname: Aga
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Behl
authors.affiliation: Department of Biochemistry, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
authors.forename: Shakir
authors.initials: S
authors.lastname: Ali
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
authors.forename: Shashank Kumar
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Natural Product Microbes Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
authors.forename: Subhash Chandra
authors.initials: SC
authors.lastname: Taneja
authors.affiliation: Natural Product Microbes Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
authors.forename: Bhahwal Ali
authors.initials: BA
authors.lastname: Shah
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
authors.forename: Ajit Kumar
authors.initials: AK
authors.lastname: Saxena
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
authors.forename: Dilip Manikrao
authors.initials: DM
authors.lastname: Mondhe
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India. Electronic address: ahdar@iiim.ac.in.
authors.forename: Abid
authors.initials: A
authors.lastname: Hamid
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D058990:Molecular Targeted Therapy; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D058539:Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; C499517:FOXO3 protein, human; C077951:7,8,9,10-tetrahydroazepino(2,1-b)quinazolin-12(6H)-one; C484760:PIK3CA protein, human
keywords: Apoptosis; Cancer progression; Colorectal cancer; PI3K; Quinazoline; Signalling