The role of apoptosis in therapy and prophylaxis of epithelial tumours by nonsteroidal anti-inflammatory drugs (NSAIDs)

Abstract

In addition to having anti-inflammatory activities, nonsteroidal anti-inflammatory drugs (NSAIDs) also inhibit neoplastic cell proliferation by inducing apoptosis. Diclofenac is the anti-neoplastic compound in diclofenac 3% gel (Solaraze) used for topical treatment of actinic keratosis (AK). Main target of NSAIDs seems to be the inhibition of cyclo-oxygenase-2 (COX-2), which is overexpressed in several epithelial tumours and catalyses the synthesis of prostaglandins. The precise mechanism of action of diclofenac in cutaneous cells is still unclear, but induction of apoptosis is a key effect of anti-neoplastic drugs, including NSAIDs. In this paper we give an overview of the anti-tumoural activities of NSAIDs with emphasis on induction of apoptosis. Cyclo-oxygenase-2-mediated synthesis of prostaglandin E(2) (PGE(2)) leads to activation of mitogen-activated protein kinase (MAPK), as well as phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Induction of the anti-apoptotic Bcl-2 and Mcl-1, as well as activation of the caspase-8 inhibitor cFLIP have been reported. In addition, altered lipid concentrations in the cytoplasmic membrane may modulate death receptor activities. Downregulation of both the intrinsic mitochondrial and the extrinsic pathways have been reported. Our data demonstrate induced apoptosis and activation of the caspase cascade in three of four cutaneous squamous cell carcinoma (SCC) cell lines, after treatment with diclofenac plus hyaluronic acid and diclofenac alone; one cell line remained nonresponsive. The effects were less pronounced in normal keratinocytes and cytotoxic effects were not seen. Detailed analysis of apoptosis pathways employed by diclofenac in these cells may help to improve therapeutic strategies and to overcome possible mechanisms that are involved in nonresponsiveness.

The role of cyclooxygenase-2 in the protection against apoptosis in vascular endothelial cells induced by cigarette smoking

“…COX-2 is known to have a significant role in apoptosis and cell survival in cancers (36). A higher number of apoptotic neutrophils in COX-2 deficient mice than COX-1 deficient mice suggested an anti-apoptotic role for COX-2 (37).…”

Oral acetylsalicylic acid and prevalence of actinic keratosis

“…The activity of those enzymes proved to be correlated to the expression of antiapoptotic proteins of the Bcl2 family. 12,13 A decrease in the formation of UV-induced skin tumors in mice that received celecoxib (89% reduction) or indomethacin (78% reduction) was observed. 37,38 A reduction in more than 50% of UVR-induced skin tumors in naked mice receiving nimesulide -a selective inhibitor of COX-2 -was also observed.…”

“…29,36 Similarly, in studies with AINE in colon cancer, a production of angiogenic factors dependent on the activity of COX-2 was observed. 13 In addition to stimulating cell proliferation and angiogenesis, the elevation of COX-2 is related to the resistance to apoptosis in various tumors, such as the colon, breast, lung, and prostate tumors. The activity of those enzymes proved to be correlated to the expression of antiapoptotic proteins of the Bcl2 family.…”

Actinic cheilitis: a case report and a review of the literature

“…Positive clinical success with the use of anti-inflammatory for the treatment of actinic cheilitis is reported in the literature by various authors [14,15,21,22]. The use of the non-steroidal anti-inflammatory drug diclofenac in the treatment and prevention of the malignization of actinic cheilitis is explained by the authors for its possible anticancer effect on inhibiting cyclooxygenase (COX-1 and COX-2) [23]. It is also important to remember that the oxidative stress caused by the inflammatory process can damage the cell DNA, that chronic inflammation increases the risk of carcinogenesis [24] and that inflammation may promote the progression from AC to squamous cell carcinoma [25].…”