title: Elucidation of structure-activity relationship of 2-quinolone derivatives and exploration of their antitumor potential through Bax-induced apoptotic pathway.
abstract: 3-Aryl-2-quinolone derivates were extensively investigated for their inhibition of farnesyl transferase. Taking this as a cue, we studied the other possible mechanism of antitumor activity of 2-quinolone derivates. A series of new 2-quinolone derivatives have been synthesized and screened for their cytotoxicity by trypan blue assay on Ehrlich ascites carcinoma cells and MTT assay on MCF-7 cells. Compound 1a (nJST) was found to be more effective in both studies with the lowest CTC(50) value among all nine synthesized compounds. This compound was further screened on four different cell lines, viz. human breast adenocarcinoma (MCF-7, MDA-MB-231), colon cancer (HCT-15), murine melanoma (B16F10) cell lines for 24 and 48 h. The CTC(50) value of the compound was found to be <10 μm. Compound 1a induced DNA damage which was revealed by DNA fragmentation studies and further confirmed by nuclear staining. The compound also showed significant elevation in Bax and reduction Bcl-2 gene expression levels. Acute toxicity study in mice indicated that the compound is safe till 2000 mg/kg. Two different doses 50 and 100 mg/kg were selected and studied in Ehrlich ascites carcinoma model of cancer and have shown significant improvement in survival time and hematological parameters.
authors.affiliation: Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal-576104, Karnataka, India.
authors.forename: Nitesh
authors.initials: N
authors.lastname: Kumar
authors.forename: Vasanth P
authors.initials: VP
authors.lastname: Raj
authors.forename: B S
authors.initials: BS
authors.lastname: Jayshree
authors.forename: Sidhartha S
authors.initials: SS
authors.lastname: Kar
authors.forename: Arvind
authors.initials: A
authors.lastname: Anandam
authors.forename: Seeja
authors.initials: S
authors.lastname: Thomas
authors.forename: Prateek
authors.initials: P
authors.lastname: Jain
authors.forename: Amita
authors.initials: A
authors.lastname: Rai
authors.forename: C M
authors.initials: CM
authors.lastname: Rao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D006912:Hydroxyquinolines; D015363:Quinolones; D051028:bcl-2-Associated X Protein; C010064:carbostyril