title: PDE2 is a novel target for attenuating tumor formation in a mouse model of UVB-induced skin carcinogenesis.
abstract: Our previous studies demonstrated that the topical application of caffeine is a potent inhibitor of UVB-induced carcinogenesis and selectively increases apoptosis in tumors but not in non-tumor areas of the epidermis in mice that are at a high risk for developing skin cancer. While this effect is mainly through a p53 independent pathway, the mechanism by which caffeine inhibits skin tumor formation has not been fully elucidated. Since caffeine is a non-specific phosphodiesterase inhibitor, we investigated the effects of several PDE inhibitors on the formation of sunburn cells in mouse skin after an acute exposure to ultraviolet light B (UVB). The topical application of a PDE2 inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA hydrochloride), stimulated epidermal apoptosis compared to control (P<0.01) and to a greater extent than caffeine whereas a PDE4 inhibitor attenuated the epidermal apoptosis compared to control (P<0.01). Since PDE2 hydrolyzes cyclic nucleotides, mainly cGMP, the effects of EHNA hydrochloride on epidermal apoptosis following UVB exposure may be mediated, in part, by increased cGMP signaling. Data demonstrated that the topical application of dibutyryl cGMP stimulated epidermal apoptosis (P<0.01) following an acute exposure to UVB. Treating UVB-pretreated mice topically with 3.1 µmole or 0.8 µmole of EHNA hydrochloride attenuated tumor formation to a greater extent than treating with 6.2 µmole caffeine when these compounds were applied once a day, five days a week for 18 weeks. These observations suggest a novel role for PDE2 in UVB-induced tumorigenesis and that PDE2 inhibitors that mediate cGMP signaling may be useful for the prevention and treatment of skin cancer.
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: Jamie J
authors.initials: JJ
authors.lastname: Bernard
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: You-Rong
authors.initials: YR
authors.lastname: Lou
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: Qing-Yun
authors.initials: QY
authors.lastname: Peng
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: Yao-Ping
authors.initials: YP
authors.lastname: Lu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002110:Caffeine / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects* / Q000528:radiation effects*; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D005260:Female; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D009712:Nucleotides, Cyclic / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D009712:Nucleotides, Cyclic; D058988:Phosphodiesterase 4 Inhibitors; D002110:Caffeine; C010192:9-(2-hydroxy-3-nonyl)adenine; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D000225:Adenine