title: Fluorescent epigenetic small molecule induces expression of the tumor suppressor ras-association domain family 1A and inhibits human prostate xenograft.
abstract: Epigenetic silencing of Ras-association domain family 1A (RASSF1A) protein in cancer cells results in a disruption of cell cycle control, genetic instability, enhanced cell motility, and apoptotic resistance. Ectopic expression of RASSF1A reverses this tumorigenic phenotype. Thus, small molecules with the ability to restore RASSF1A expression may represent a new class of therapeutic agents. Recently, we designed and synthesized a fluorescent carbazole analogue of mahanine (alkaloid from Murraya koenigii) that restored RASSF1A mRNA expression. Our fluorescent lead compound up-regulated RASSF1A in vitro, potently inhibited human prostate cancer cell proliferation, and fluoresced at a visible wavelength, allowing for the observation of intracellular distribution. The small molecule lead was not acutely toxic up to 550 mg/kg, and dosing at 10 mg/kg reduced human xenograft tumor volume by about 40%.
authors.affiliation: Department of Oncology, Georgetown University, 3970 Reservoir Road NW, Washington, DC 20057, USA.
authors.forename: Kathryn D
authors.initials: KD
authors.lastname: Sheikh
authors.forename: Partha P
authors.initials: PP
authors.lastname: Banerjee
authors.forename: Shankar
authors.initials: S
authors.lastname: Jagadeesh
authors.forename: Scott C
authors.initials: SC
authors.lastname: Grindrod
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Mikell
authors.initials: M
authors.lastname: Paige
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005453:Fluorescence; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008956:Models, Chemical; D015394:Molecular Structure; D032101:Murraya / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D002227:Carbazoles; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; C465290:mahanine; D019938:Cyclin D1; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases