title: Monoamine oxidase A inhibitor-near-infrared dye conjugate reduces prostate tumor growth.
abstract: Development of anti-cancer agents with high tumor-targeting specificity and efficacy is critical for modern multidisciplinary cancer research. Monoamine oxidase A (MAOA), a mitochondria-bound enzyme, degrades monoamine neurotransmitters and dietary monoamines. Recent evidence suggests a correlation between increased MAOA expression and prostate cancer (PCa) progression with poor outcomes for patients. MAOA induces epithelial-mesenchymal transition (EMT) and augments hypoxic effects by producing excess reactive oxygen species. Thus, development of MAOA inhibitors which selectively target tumors becomes an important goal in cancer pharmacology. Here we describe the design, synthesis, and in vitro and in vivo evaluation of NMI, a conjugate that combines a near-infrared dye for tumor targeting with the moiety derived from the MAOA inhibitor clorgyline. NMI inhibits MAOA with low micromolar IC50, suppresses PCa cell proliferation and colony formation, and reduces migration and invasion. In mouse PCa xenografts, NMI targets tumors with no detectable accumulation in normal tissues, providing effective reduction of the tumor burden. Analysis of tumor specimens shows reduction in Ki-67(+) and CD31(+) cells, suggesting a decrease of cell proliferation and angiogenesis and an increase in M30(+) cells, indicating increased apoptosis. Gene expression profiles of tumors treated with NMI demonstrate reduced expression of oncogenes FOS, JUN, NFKB, and MYC and cell cycle regulators CCND1, CCNE1, and CDK4/6, along with increases in the levels of tumor suppressor gene TP53, cell cycle inhibitors CDKN1A and CDKN2A, and MAOA-downstream genes that promote EMT, tumor hypoxia, cancer cell migration, and invasion. These data suggest that NMI exerts its effect through tumor-targeted delivery of a MAOA-inactivating group, making NMI a valuable anti-tumor agent.
authors.affiliation: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center , Los Angeles, California 90048, United States.
authors.forename: Jason Boyang
authors.initials: JB
authors.lastname: Wu
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Lin
authors.forename: John D
authors.initials: JD
authors.lastname: Gallagher
authors.forename: Swati
authors.initials: S
authors.lastname: Kushal
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.forename: Haiyen E
authors.initials: HE
authors.lastname: Zhau
authors.forename: Bogdan Z
authors.initials: BZ
authors.lastname: Olenyuk
authors.forename: Jean C
authors.initials: JC
authors.lastname: Shih
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D004396:Coloring Agents / Q000737:chemistry*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008995:Monoamine Oxidase / Q000187:drug effects*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D019265:Spectroscopy, Near-Infrared
chemical_list: D004396:Coloring Agents; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase