Monoamine Oxidase A Inhibitor–Near-Infrared Dye Conjugate Reduces Prostate Tumor GrowthJ. Am. Chem. Soc.

About

Authors
Jason Boyang Wu, Tzu-Ping Lin, John D. Gallagher, Swati Kushal, Leland W. K. Chung, Haiyen E. Zhau, Bogdan Z. Olenyuk, Jean C. Shih
Year
2015
DOI
10.1021/ja512613j
Subject
Chemistry (all) / Colloid and Surface Chemistry / Biochemistry / Catalysis

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Article

Monoamine Oxidase A Inhibitor – Near-Infrared

Dye Conjugate Reduces Prostate Tumor Growth

Jason Boyang Wu, Tzu-Ping Lin, John David Gallagher, Swati Kushal,

Leland W. K. Chung, Haiyen Zhau, Bogdan Z Olenyuk, and Jean C. Shih

J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja512613j • Publication Date (Web): 13 Jan 2015

Downloaded from http://pubs.acs.org on January 21, 2015

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Monoamine Oxidase A Inhibitor – Near-Infrared

Dye Conjugate Reduces Prostate Tumor Growth

Jason Boyang Wu, †

Tzu-Ping Lin, §,‡

John D. Gallagher, ‡

Swati Kushal, ‡

Leland W.K. Chung, †

Haiyen E. Zhau, *,†

Bogdan Z. Olenyuk, *, ‡,ǁ and Jean C. Shih *, ‡, ⊥

Addresses: †

Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive

Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, U.S.A. ‡

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of

Southern California, Los Angeles, CA 90089, U.S.A. ⊥Department of Cell and Neurobiology, Keck School of Medicine, University of Southern

California, 1975 Zonal Ave., Los Angeles, CA 90033, U.S.A. ǁ

USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90033,

U.S.A. §

Current addresses: Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan 11217, R.O.C., and Department of Urology, School of Medicine, and Shu-Tien Urological

Research Center, National Yang-Ming University, Taipei, Taiwan 11217, R.O.C. *Corresponding authors:

Jean C. Shih, Department of Pharmacology and Pharmaceutical Sciences, 1985 Zonal Ave.,

PSC 518, Los Angeles, CA 90089, U.S.A. Tel.: +1-323-442-1441; E-mail: jcshih@usc.edu

Bogdan Z. Olenyuk, Department of Pharmacology and Pharmaceutical Sciences, 1985 Zonal

Ave., PSC B15C, Los Angeles, CA 90089, U.S.A. Tel.: +1-323-442-1390; E-mail: bogdan@usc.edu.

Haiyen E. Zhau, Uro-Oncology Research Program, Department of Medicine, Samuel Oschin

Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, U.S.A.

Tel.: +1-310-423-5992; E-mail: haiyen.zhau@cshs.org

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Abstract

Development of anticancer agents with high tumor-targeting specificity and efficacy are critical goals of modern multidisciplinary cancer research. Monoamine oxidase A (MAOA), a mitochondria-bound enzyme, degrades monoamine neurotransmitters and dietary monoamines.

Recent evidence suggests 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, in vitro and in vivo evaluation of NMI, a conjugate that combines a near-infrared dye for tumor targeting with the moiety derived from MAOA inhibitor clorgyline. NMI inhibits MAOA with low micromolar

IC50, suppresses PCa cell proliferation, colony formation and reduces migration and invasion. In mouse PCa xenografts, NMI targets tumor 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 decrease of cell proliferation and angiogenesis, and increase in M30 + cells, indicating increased apoptosis. Gene expression profiles of tumors treated with NMI demonstrate reduced expression of oncogenes FOS, JUN, NFKB, MYC, and cell cycle regulators CCND1, CCNE1, CDK4/6, and increase 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 MAOA-inactivating group, making NMI a valuable anti-tumor agent.