title: Nitric oxide-releasing sulindac is a novel skin cancer chemopreventive agent for UVB-induced photocarcinogenesis.
abstract: Nitric oxide (NO)-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) which have been synthesized to reduce gastro-intestinal and cardiovascular toxicities of NSAIDs, possess anti-proliferative, pro-apoptotic and anti-cancer activities. Here, we show that NO-sulindac inhibited UVB-induced skin tumorigenesis in SKH-1 hairless mice. Topical application of NO-sulindac reduced tumor incidence, number (p<0.05) and volume (p<0.005) as compared to UVB (alone)-irradiated vehicle-treated mice. An increase in TUNEL-positive cells in skin lesions was accompanied by the enhanced Bax:Bcl-2 ratio. The expression of pro-apoptotic Bax was increased whereas anti-apoptotic Bcl-2 reduced. However, proliferation was identified as the major target of NO-sulindac in this study. A reduced expression of PCNA and cyclin D1 associated with the dampening of cell cycle progression was observed. The mechanism of this inhibition was related to the reduction in UVB-induced Notch signaling pathway. UVB-induced inflammatory responses were diminished by NO-sulindac as observed by a remarkable reduction in the levels of phosphorylated MAP Kinases Erk1/2, p38 and JNK1/2. In this regard, NO-sulindac also inhibited NFκB by enhancing IκBα as evidenced by the reduced expression of iNOS and COX-2, the direct NFκB transcription target proteins. NO-sulindac significantly diminished the progression of benign lesions to invasive carcinomas by suppressing the tumor aggressiveness and retarding epithelial-mesenchymal transition. A marked decrease in the expression of mesenchymal markers such as Fibronectin, N-cadherin, SNAI, Slug and Twist and an increase in epithelial cell polarity marker E-cadherin were noted in NO-sulindac-treated tumors. Our data suggest that NO-sulindac is a potent inhibitor of UVB-induced skin carcinogenesis and acts by targeting proliferation-regulatory pathways.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, 1530 3rd Avenue South, VH509, Birmingham, AL 35294-0019, USA.
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Chaudhary
authors.forename: Tripti
authors.initials: T
authors.lastname: Singh
authors.forename: Puneet
authors.initials: P
authors.lastname: Kapur
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.forename: Aadithya
authors.initials: A
authors.lastname: Arumugam
authors.forename: Craig A
authors.initials: CA
authors.lastname: Elmets
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D009569:Nitric Oxide / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000517:prevention & control*; D013467:Sulindac / Q000494:pharmacology / Q000627:therapeutic use*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D000970:Antineoplastic Agents; D013467:Sulindac; D009569:Nitric Oxide