title: NCI in vitro and in silico anticancer screen, cell cycle pertubation and apoptosis-inducing potential of new acylated, benzylidene and isopropylidene derivatives of andrographolide.
abstract: Andrographolide (AGP) is the main bioactive constituent isolated from the traditional medicinal, Andrographis paniculata which contributes towards its various biological activities, including anticancer property. In this study, a series of new AGP derivatives were semi-synthesised and screened against the NCI in vitro 60 cell lines. From the screening results, we had identified SRS07 as the most potent AGP derivative, against breast and colon cancer cell lines. Subsequently, SRS07 was tested for its capability to induce cell cycle arrest and apoptosis in MCF-7 and HCT116 cancer cells. SRS07 effectively induced G1 cell cycle arrest in both cell lines and ultimately apoptosis by inducing DNA fragmentation in HCT116 cells. The apoptotic cell death induced by SRS07 was confirmed via FITC Annexin-V double staining. Western blot analysis of SRS07-treated HCT116 cells revealed that the compound induced apoptosis be activating caspase 8 which in turn cleaved Bid to t-Bid to initiate cell death cascade. Prediction of the possible mode of action of SRS07 by utilising NCI COMPARE analysis failed to reveal a distinct mechanism category. Hence, it is speculated that SRS07 possesses novel mechanism of action. In conclusion, SRS07 demonstrated superior in vitro anticancer profiles and emerged as a potential lead anticancer candidate.
authors.affiliation: Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia.
authors.forename: Charng Choon
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia.
authors.forename: Sreenivasa Rao
authors.initials: SR
authors.lastname: Sagineedu
authors.affiliation: Neurology Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia.
authors.forename: Shariful Hasan
authors.initials: SH
authors.lastname: Sumon
authors.affiliation: Histopathology Unit, Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia.
authors.forename: Shiran Mohamad
authors.initials: SM
authors.lastname: Sidik
authors.affiliation: Institute of Cancer Therapeutics, University of Bradford, BD7 1DP Bradford, United Kingdom.
authors.forename: Roger
authors.initials: R
authors.lastname: Phillips
authors.affiliation: Institute of Cancer Therapeutics, University of Bradford, BD7 1DP Bradford, United Kingdom.
authors.forename: Nordin H
authors.initials: NH
authors.lastname: Lajis
authors.affiliation: Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia; Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400 Selangor, Malaysia. Electronic address: jstanslas@yahoo.co.uk.
authors.forename: Johnson
authors.initials: J
authors.lastname: Stanslas
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D045325:HCT116 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D061986:MCF-7 Cells; D008958:Models, Molecular; D054547:National Cancer Institute (U.S.); D009369:Neoplasms / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D001597:Benzylidene Compounds; D004224:Diterpenes; D006575:Heterocyclic Compounds, 3-Ring; C000598752:SRS07 compound; C030419:andrographolide; C505530:CASP8 protein, human; D053181:Caspase 8; D015107:4-Butyrolactone
keywords: Andrographolide derivatives; Apoptosis; Cell cycle; In silico; NCI