Poly(adenosine diphosphate-ribose) polymerase-1 expression in cutaneous malignant melanomas as a new molecular marker of aggressive tumor.

Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of enzymes, which catalyses poly (ADP-ribosyl)ation of DNA-binding proteins and directly involved in genomic stability, DNA repair, and apoptosis. In this study, we evaluated the immunomorphology of PARP-1 in melanoma and its prognostic importance. We studied PARP-1 expression by immunohistochemistry in a selected series of 54 primary cutaneous malignant melanoma (CMM). The findings of the present study suggest that the neoplastic progression toward the invasive (both horizontal and vertical) growth phase of CMM cells is characterized by the loss of cleavage of PARP-1, probably signaling an imbalance of the apoptotic process in these cells and leading to further gain to aggression. Over-expression of full-length PARP-1 was correlated with recurrence and/or progression of the disease and so act as a promising new biological marker of CMM. Our study represents the evidence of a direct correlation between the PARP-1-mediated apoptotic process and the biologic behavior of CMM.

Reduction of acute photodamage in skin by topical application of a novel PARP inhibitor.

The ultraviolet (UV) components of sunlight induce damage to the DNA in skin cells, which is considered to be the initiating step in the harmful biological effects of UV radiation. Repair of DNA damage results in the formation of single-strand DNA breaks, which activate the nuclear poly(ADP-ribose) polymerase (PARP). Overactivation of PARP worsens the oxidative cell damage and impairs the energy metabolism, raising the possibility that moderation of PARP activation following DNA damage may protect skin cells from UV radiation. The topical effects of the novel PARP inhibitor O-(3-pyperidino-2-hydroxy-1-propyl) pyridine-3-carboxylic acid amidoxime monohydrochloride (BGP-15M) were investigated on UV-induced skin damage in a hairless mouse model. For evaluation of the UV-induced acute photodamage to the skin and the potential protective effect of BGP-15M, DNA injury was detected by measuring the formation of single-strand DNA breaks and counting the resulting sunburn (apoptotic) cells. The ADP-ribosylation of PARP was assessed by Western blot analysis and then quantified. In addition, the UV-induced immunosuppression was investigated by the immunostaining of tumor necrosis factor alpha and interleukin-10 expressions in epidermal cells. The signs of inflammation were examined clinically and histochemically. Besides its primary effect in decreasing the activity of nuclear PARP, topically applied BGP-15M proved to be protective against solar and artificial UV radiation-induced acute skin damage. The DNA injury was decreased (P<0.01). An inhibition of immunosuppression was observed by down-regulation of the epidermal production of cytokines IL-10 and TNFalpha. In the mouse skin, clinical or histological signs of UV-induced inflammation could not be observed. These data suggest that BGP-15M directly interferes with UV-induced cellular processes and modifies the activity of PARP. The effects provided by topical application of the new PARP-regulator BGP-15M indicate that it may be a novel type of agent in photoprotection of the skin.