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, anti-proliferative and apoptosis-inducing effects in tumor cells. Here 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 to 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 pro-apoptotic Bax and decreased expression of anti-apoptotic 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.

Metformin, an Antidiabetic Agent Reduces Growth of Cutaneous Squamous Cell Carcinoma by Targeting mTOR Signaling Pathway†

“…Donnini et al reported a similar inhibition of iNOS and COX-2 associated with a reduction in SCC tumor growth (27). In a previous study we also showed that COX-2 inhibitors reduce UVB-induced skin carcinogenesis (28, 29). …”

Nitric oxide-releasing sulindac is a novel skin cancer chemopreventive agent for UVB-induced photocarcinogenesis

“…The UV irradiation unit was equipped with six Philips Ultravoilet B TL 40W/12RS lamps. Furthermore, we also used a Kodacel cellulose film (Kodacel TA401 / 407) to eliminate any UVC as described earlier (Singh et al , 2012). …”

“…In addition to UVB irradiation, group II and III mice received twice weekly topical treatments (30 min prior to UVB irradiation) with either vehicle (acetone) or NO-sulindac (5 mg/mouse dissolved in 200μl acetone) respectively. The numbers and volume (using electronic Vernier Calipers) of tumors in each animal were recorded on a weekly basis as described earlier (Singh et al , 2012). The selection of the dose of NO-sulindac is based on our previously published study related to photo-protective effects of sulindac (Athar et al , 2004).…”

“…Interestingly, similar to their parent agents, NO-NSAIDsalso have anti-proliferative and anti-tumor effects (Williams et al , 2004; Stewart et al , 2009; Singh et al , 2012). These agents showed efficacy against a variety of cancer-types.…”

Phosphodiesterase Type 5 as a Candidate Therapeutic Target in Cancers

“…Moreover, it has been demonstrated that exisulind suppressed 1-methyl-1-nitrosourea (MNU)-induced mammary carcinogenesis [92], azoxymethane-induced colon carcinogenesis [93], and Nbutyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder carcinogenesis [8] in rats, and at concentrations that were well tolerated by the animals. Exisulind also inhibited UVB-induced skin tumor development 'in vivo' by inducing apoptosis and reducing proliferation as well as epithelial-mesenchymal transition in tumor keratinocytes [94].…”