title: Experimental therapy of ovarian cancer with synthetic makaluvamine analog: in vitro and in vivo anticancer activity and molecular mechanisms of action.
abstract: The present study was designed to determine the biological effects of novel marine alkaloid analog 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) on human ovarian cancer cells for its anti-tumor potential and the underlying mechanisms as a novel chemotherapeutic agent. Human ovarian cancer cells (A2780 and OVCAR-3), and Immortalized non-tumorigenic human Ovarian Surface Epithelial cells (IOSE-144), were exposed to FBA-TPQ for initial cytotoxicity evaluation (via MTS assay kit, Promega). The detailed in-vitro (cell level) and in-vivo (animal model) studies on the antitumor effects and possible underlying mechanisms of action of the compounds were then performed. FBA-TPQ exerted potent cytotoxicity against human ovarian cancer A2780 and OVCAR-3 cells as an effective inhibitor of cell growth and proliferation, while exerting lesser effects on non-tumorigenic IOSE-144 cells. Further study in the more sensitive OVCAR-3 cell line showed that it could potently induce cell apoptosis (Annexin V-FITC assay), G2/M cell cycle arrest (PI staining analysis) and also dose-dependently inhibit OVCAR-3 xenograft tumors' growth on female athymic nude mice (BALB/c, nu/nu). Mechanistic studies (both in vitro and in vivo) revealed that FBA-TPQ might exert its activity through Reactive Oxygen Species (ROS)-associated activation of the death receptor, p53-MDM2, and PI3K-Akt pathways in OVCAR-3 cells, which is in accordance with in vitro microarray (Human genome microarrays, Agilent) data analysis (GEO accession number: GSE25317). In conclusion, FBA-TPQ exhibits significant anticancer activity against ovarian cancer cells, with minimal toxicity to non-tumorigenic human IOSE-144 cells, indicating that it may be a potential therapeutic agent for ovarian cancer.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.forename: He
authors.initials: H
authors.lastname: Guo
authors.forename: Yanling
authors.initials: Y
authors.lastname: Liu
authors.forename: Pingting
authors.initials: P
authors.lastname: Hu
authors.forename: Xinying
authors.initials: X
authors.lastname: Yang
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.forename: Shichao
authors.initials: S
authors.lastname: Ge
authors.forename: Sadanandan E
authors.initials: SE
authors.lastname: Velu
authors.forename: Dwayaja H
authors.initials: DH
authors.lastname: Nadkarni
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D010051:Ovarian Neoplasms / Q000473:pathology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C550613:7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one; D000970:Antineoplastic Agents; D011758:Pyrroles; D015363:Quinolones