title: Andrographolide inhibits prostate cancer by targeting cell cycle regulators, CXCR3 and CXCR7 chemokine receptors.
abstract: Despite state of the art cancer diagnostics and therapies offered in clinic, prostate cancer (PCa) remains the second leading cause of cancer-related deaths. Hence, more robust therapeutic/preventive regimes are required to combat this lethal disease. In the current study, we have tested the efficacy of Andrographolide (AG), a bioactive diterpenoid isolated from Andrographis paniculata, against PCa. This natural agent selectively affects PCa cell viability in a dose and time-dependent manner, without affecting primary prostate epithelial cells. Furthermore, AG showed differential effect on cell cycle phases in LNCaP, C4-2b and PC3 cells compared to retinoblastoma protein (RB(-/-)) and CDKN2A lacking DU-145 cells. G2/M transition was blocked in LNCaP, C4-2b and PC3 after AG treatment whereas DU-145 cells failed to transit G1/S phase. This difference was primarily due to differential activation of cell cycle regulators in these cell lines. Levels of cyclin A2 after AG treatment increased in all PCa cells line. Cyclin B1 levels increased in LNCaP and PC3, decreased in C4-2b and showed no difference in DU-145 cells after AG treatment. AG decreased cyclin E2 levels only in PC3 and DU-145 cells. It also altered Rb, H3, Wee1 and CDC2 phosphorylation in PCa cells. Intriguingly, AG reduced cell viability and the ability of PCa cells to migrate via modulating CXCL11 and CXCR3 and CXCR7 expression. The significant impact of AG on cellular and molecular processes involved in PCa progression suggests its potential use as a therapeutic and/or preventive agent for PCa.
authors.affiliation: a Department of Microbiology , Biochemistry and Immunology, Morehouse School of Medicine , Atlanta , GA , USA.
authors.forename: Hina
authors.initials: H
authors.lastname: Mir
authors.affiliation: a Department of Microbiology , Biochemistry and Immunology, Morehouse School of Medicine , Atlanta , GA , USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Kapur
authors.affiliation: a Department of Microbiology , Biochemistry and Immunology, Morehouse School of Medicine , Atlanta , GA , USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Singh
authors.affiliation: b Department of Medicine , Division of Hematology and Oncology, University of Alabama of Birmingham , Birmingham , AL , USA.
authors.forename: Guru
authors.initials: G
authors.lastname: Sonpavde
authors.affiliation: a Department of Microbiology , Biochemistry and Immunology, Morehouse School of Medicine , Atlanta , GA , USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Lillard
authors.affiliation: a Department of Microbiology , Biochemistry and Immunology, Morehouse School of Medicine , Atlanta , GA , USA.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Singh
mesh_terms: D035685:Andrographis / Q000737:chemistry*; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054371:Chemokine CXCL11 / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000737:chemistry; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D054387:Receptors, CXCR / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C501896:ACKR3 protein, human; D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; C503688:CCNE2 protein, human; C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D018797:Cell Cycle Proteins; D054371:Chemokine CXCL11; D056744:Cyclin B1; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D004224:Diterpenes; D006657:Histones; D009687:Nuclear Proteins; D010936:Plant Extracts; D054387:Receptors, CXCR; D054367:Receptors, CXCR3; D016160:Retinoblastoma Protein; C030419:andrographolide; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases
keywords: Andrographolide; CXCL11; CXCR3; CXCR7; Cell cycle; Cyclins; chemokine; chemokine receptor and prostate cancer