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.

Caffeine promotes anti-tumor immune response during tumor initiation: Involvement of the adenosine A2A receptor

“…Caffeine is a non-selective phosphodiesterase (PDE) inhibitor. It acts by competing with adenine for access to the catalytic site of PDEs and prevents PDEs from inactivating cAMP or cGMP [37]. High intracellular level of cAMP and cGMP could arrest growth, induce apoptosis and attenuate cancer cell migration [38,39].…”

Sustained Regression of Hydroxycarbamide Induced Actinic Keratoses after Switching to Anagrelide

“…PDE3A is expressed ~40% more in sun-exposed (tibial) compared to sun-protected skin [ 14 ] underscoring the need to evaluate its expression in keratinocytic carcinomas, including AK. Likewise, in an experimental mouse model, cilostamide, a PDE3 inhibitor, increased apoptosis in UV damaged keratinocytes by 29%, while other PDE inhibitors (PDE2 inhibitors) demonstrated even more pronounced effects [ 15 ].…”

Mirabilis Jalapa L. Protein as Inductor of Apoptosis on UVB-induced Skin Damage in Mice

“…MJ-Protein involvement in the regulation of apoptosis is present in common with caffeine. Topical application of caffeine has also been shown to increase the apoptotic sunburn cells of skin, 16,17 so that cells undergoing DNA damage will be faster and more eliminated from skin. It is well known that the regulation of apoptosis may be a decisive factor protection against UV radiationinduced carsinogenesis.…”