A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model.
High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1-acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression.
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, WI 53792-5669, USA. hsb@medicine.wisc.edu
Hirak S
HS
Basu
Todd A
TA
Thompson
Dawn R
DR
Church
Cynthia C
CC
Clower
Farideh
F
Mehraein-Ghomi
Corey A
CA
Amlong
Christopher T
CT
Martin
Patrick M
PM
Woster
Mary J
MJ
Lindstrom
George
G
Wilding
D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000728:Androgens / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011700:Putrescine / Q000031:analogs & derivatives* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D000728:Androgens; D004791:Enzyme Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011700:Putrescine; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase; C044445:MDL 72527