Selective induction of apoptosis in the hamster flank sebaceous gland organ by a topical liposome 5-alpha-reductase inhibitor: a treatment strategy for acne.
Acne is a very widespread cosmesis problem. Isotretinoin, a synthetic oral retinoid is used to treat acne, which is androgen dependent. Numerous side-effects occur from this treatment. 5-alpha-Reductase plays a critical role in normal and pathological androgen-dependent processes. We have taken the approach to develop a selective, effective, topically-applied 5-alpha-reductase inhibitor to modify unwanted or pathological processes in the pilosebaceous unit such as acne. Toward this goal, we have previously developed a selective liposome hair follicle targeting system. We demonstrate in this report that the 5-alpha-reductase inhibitor N,N-diethyl-4-methyl-3-oxo-4-aza-5alpha-androstane-17beta-carboxamide (4-MA) incorporated into liposomes induces apoptosis and inhibits growth of the dihydrotestosterone (DHT)-dependent hamster flank organ sebaceous gland. We have compared topical application of liposome 4-MA and solvent-formulated 4-MA and observed selective efficacy of topical application of liposome 4-MA by the reduction of size and induction of apoptosis only in the treated hamster flank organ. Apoptosis induced by liposome 4-MA in the treated flank organ sebaceous gland cells was observed both by assays for DNA fragments (transferase deoxytidyl uridine end labeling) and by observation of condensed and fragmented nuclei. When 4-MA was topically applied formulated in ethanol and glycerol without liposomes, the selective efficacy was lost. Liposome 4-MA did not significantly affect prostate weight, testosterone/DHT ratios or bodyweight gain compared to controls indicating safety as well as efficacy of topical application of liposome 4-MA for pathological processes such as acne.
Li
Lingna
L
AntiCancer, Inc, University of California San Diego, San Diego, California 92111, USA.
Tang
Li
L
Baranov
Eugene
E
Yang
Meng
M
Amoh
Yasuyuki
Y
Katsuoka
Kensei
K
Hoffman
Robert M
RM
D000152:Acne Vulgaris / Q000188:drug therapy* / Q000201:enzymology; D000287:Administration, Topical; D000818:Animals; D017209:Apoptosis; D001378:Azasteroids / Q000008:administration & dosage / Q000627:therapeutic use*; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors*; D006224:Cricetinae; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008081:Liposomes; D008297:Male; D011467:Prostate / Q000187:drug effects; D012627:Sebaceous Glands / Q000187:drug effects* / Q000201:enzymology
D001378:Azasteroids; D008081:Liposomes; D013196:Dihydrotestosterone; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one; D042944:Cholestenone 5 alpha-Reductase