NO-releasing nonsteroidal anti-inflammatory drugs (NO-
NSAIDs) have been shown to have anti-inflammatory, antiproliferative and apoptosis-inducing effects in
tumor cells. Herein, we have investigated the effects of NO-
exisulind on the growth of UVB-induced skin
tumor development in a murine model. We found that the topical treatment with NO-
exisulind significantly reduced UVB-induced
tumors in SKH-1 hairless mice. The
tumors/
tumor bearing mouse, the number of
tumors/mouse and
tumor volume/mouse decreased significantly (P < 0.05) as compared with vehicle-treated and UVB-irradiated positive controls. Consistently, NO-
exisulind-treated animals showed reduced expression of proliferation markers, such as
PCNA and
cyclin D1. These mice also manifested increased expression of proapoptotic Bax and decreased expression of antiapoptotic Bcl2 with an increase in the number of TUNEL-positive cells in
tumors. We also investigated whether NO-
exisulind-treated
tumors are less invasive and progress less efficiently from benign to malignant
carcinomas. For this,
tumors were stained for various epithelial-mesenchymal transition (EMT) markers. NO-
exisulind decreased the expression of mesenchymal markers, such as
Fibronectin,
N-cadherin, SNAI, Slug and Twist and enhanced the epithelial marker
E-cadherin. Similarly, UVB-induced phosphorylation of Erk1/2 and p38 was decreased in NO-
exisulind-treated animals. These data suggest that NO-
exisulind reduces
tumor growth and inhibits
tumor progression by blocking proliferation, inducing apoptosis and reducing EMT.