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.