There are conflicting epidemiologic data on whether chronic aspirin (ASA) use may reduce melanoma risk in humans. Potential anticancer effects of ASA may be mediated by its ability to suppress prostaglandin E (PGE) production and activate 5'-adenosine monophosphate-activated protein kinase (AMPK). We investigated the inhibitory effects of ASA in a panel of melanoma and transformed melanocyte cell lines, and on tumor growth in a preclinical model. ASA and the COX-2 inhibitor celecoxib did not affect melanoma cell viability, but significantly reduced colony formation, cell motility, and pigmentation (melanin production) at concentrations of 1 mmol/L and 20 μmol/L, respectively. ASA-mediated inhibition of cell migration and pigmentation was rescued by exogenous PGE or Compound C, which inhibits AMPK activation. Levels of tyrosinase, MITF, and p-ERK were unaffected by ASA exposure. Following a single oral dose of 0.4 mg ASA to NOD/SCID mice, salicylate was detected in plasma and skin at 4 hours and PGE levels were reduced up to 24 hours. Some human melanoma tumors xenografted into NOD/SCID mice were sensitive to chronic daily ASA administration, exhibiting reduced growth and proliferation. ASA-treated mice bearing sensitive and resistant tumors exhibited both decreased PGE in plasma and tumors and increased phosphorylated AMPK in tumors. We conclude that ASA inhibits colony formation, cell motility, and pigmentation through suppression of PGE and activation of AMPK and reduces growth of some melanoma tumors This preclinical model could be used for further tumor and biomarker studies to support future melanoma chemoprevention trials in humans..

We used two experimental paradigms to examine the influence of the neurotrophins, NGF, EGF, and bFGF on normal neuroblast survival and also after ethanol insult. In the first paradigm, chick embryos received in ovo at embryonic day 1 and 2 (E1 and E2) saline (control) ethanol (10mg/50 microliters/day), NGF (50 ng/50 microliters/day), or EGF (25 ng/50 microliters/day), or ethanol+NGF or EGF. At E3, cultures were prepared from whole embryos separately from each group. At C2, all cultures were labeled with [3H]thymidine and assessed for effects or neuronal survival. In the second paradigm, cultures were prepared from 3-day-old whole embryos and at C0, cultures were treated with either ethanol (50 mM) alone, NGF (50 ng/ml) alone, EGF (25 ng/ml) alone, bFGF (50 ng/ml) alone, or were treated concomitantly with ethanol plus one of the neurotrophins; control had only the culture medium, DMEM + 5% FBS. We obtained the following findings. 1) Cultures derived from embryos treated with either of the three neurotrophins exhibited a higher neuronal survival as compared to controls (1st paradigm). 2) The survival-promoting effect was also observed when the neurotrophins were added directly to the cultures (2nd paradigm). 3) As reported previously, cultures derived from ethanol-treated embryos exhibited a marked decline in neuronal survival as compared to controls. 4) All three neurotrophins attenuated the decline in neuronal survival produced by ethanol. The 'rescuing' effects of the neurotrophins support our early hypothesis that ethanol administration during early neurogenesis interferes with microenvironmental trophic signals essential for neuroblast survival and differentiation.

UVR promotes skin cancer through multiple mechanisms, including induction of inflammation, oxidative stress, and DNA damage such as 8-oxoguanine and cyclobutane pyrimidine dimers. We investigated whether the anti-inflammatory activities of aspirin (acetylsalicylic acid [ASA]) could protect against UVB-induced DNA damage and skin carcinogenesis. ASA reduced UVB-induced 8-oxoguanine and cyclobutane pyrimidine dimers in Melan-A melanocytes and HaCaT keratinocytes. Skin from UVB-irradiated C57BL/6 mice receiving 0.4 mg ASA daily by gavage exhibited less inflammation, fewer sunburn cells, and reduced 8-oxoguanine lesions than skin from irradiated control animals. ASA similarly reduced UVB-induced sunburn cells, 8-oxoguanine, and cyclobutane pyrimidine dimer lesions in skin of melanoma-prone TN 61R mice, and this was associated with decreased prostaglandin E 2 in plasma and skin. These effects of ASA, however, did not delay melanoma onset in TN 61R mice exposed to a single neonatal dose of UVB. In SKH1-E mice prone to squamous cell carcinoma, ASA reduced plasma and skin prostaglandin E 2 levels and indices of UVB-induced DNA damage and delayed squamous cell carcinoma onset induced by chronic UVB. These results indicate that ASA can protect against UVB-induced inflammation in skin and reduce UVB-induced DNA damage in both melanocytes and keratinocytes. These effects translated into greater chemopreventive efficacy for UVB-induced squamous cell carcinoma than melanoma mouse models.