title: Nitric oxide donor exisulind is an effective inhibitor of murine photocarcinogenesis.
abstract: 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.
authors.affiliation: Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Tripti
authors.initials: T
authors.lastname: Singh
authors.forename: Sandeep C
authors.initials: SC
authors.lastname: Chaudhary
authors.forename: Puneet
authors.initials: P
authors.lastname: Kapur
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
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: D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000528:radiation effects; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D008812:Mice, Hairless; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D012867:Skin / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000071250:Snail Family Transcription Factors; D012908:Snails / Q000235:genetics / Q000378:metabolism; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D014408:Biomarkers, Tumor; D015820:Cadherins; C489083:Cdh2 protein, mouse; D005353:Fibronectins; D020030:Nitric Oxide Donors; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D019938:Cyclin D1; D013467:Sulindac; C025463:sulindac sulfone