Sulindac is a nonsteroidal anti-inflammatory
drug with demonstrated potency as a chemopreventive agent in animal models of
carcinogenesis and in patients with
familial adenomatous polyposis. Because
tumor promotion is generally associated with exposure to pro-inflammatory stimuli, it is likely that
anti-inflammatory agents may have potent antitumor effects. In human skin,
sulindac reduces
bradykinin-induced
edema. In this study, we tested the hypothesis that the
cyclooxygenase inhibitor sulindac can protect against ultraviolet (UVB)-induced injury that is crucial for the induction of
cancer. Exposure of SKH-1 hairless mice to two consecutive doses of UVB (230 mJ/cm2) induces various inflammatory responses including
erythema,
edema, epidermal
hyperplasia, infiltration of polymorphonuclear leukocytes, etc. Topical application of
sulindac (1.25-5.0 mg/0.2 ml
acetone) to the dorsal skin of SKH-1 hairless mice either 1 h before or immediately after UVB exposure substantially inhibited these inflammatory responses in a dose-dependent manner.
Oral administration of
sulindac in
drinking water (160 ppm) for 15 days before and during UVB irradiation similarly reduced these inflammatory responses. These potent anti-inflammatory effects of
sulindac suggested the possibility that the
drug could inhibit signaling processes that relate to carcinogenic insult by UVB. Accordingly, studies were conducted to assess the efficacy of
sulindac in attenuating the expression of UVB-induced early surrogate molecular markers of photodamage and
carcinogenesis. UVB exposure enhanced the expression of p53, c-fos,
cyclins D1 and A, and
PCNA 24 h after irradiation. Treatment of animals with either topical or
oral administration of
sulindac largely abrogated the expression of these UVB-induced
surrogate markers. These results indicate that the
cyclooxygenase inhibitor sulindac is effective in reducing UVB-induced events relevant to
carcinogenesis and that this category of topically applied or orally administered drugs may prove to be effective chemopreventive agents for reducing the risk of photocarcinogenesis in human populations.