Perspectives of the Application of Non-Steroidal Anti-Inflammatory Drugs in Cancer Therapy: Attempts to Overcome Their Unfavorable Side Effects

SIMPLE SUMMARY: The application of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer therapy has been a widely studied topic for almost four decades. This review summarizes the information about the role of chronic inflammation in the process of carcinogenesis and the evidence regarding the anti-cancer activity of the most frequently used NSAIDs. Despite the promising results of NSAIDs, the possibilities of the practical application of this group of drugs in chemoprevention and cancer therapies on a clinical basis are still impossible due to individual side effects. The main concern is their gastrointestinal toxicity. For this reason, several strategies are still under investigation to reduce toxicity and improve the efficacy of NSAIDs. In this review, we emphasize the effectiveness of combinations of NSAIDs with chemotherapeutic drugs in in vitro and in vivo models as well as in clinical trials. We also present new concepts based on the molecular hybridization of anti-inflammatory drugs with other biologically active molecules, such as phospholipids and terpenes, as solutions for reducing NSAID side effects. The production of derivatives with enhanced biological potentials could also be carried out to target rare types of cancers. Therefore, this manuscript provides new insight into the possibilities of re-purposing NSAIDs for new, outside-the-current-scope applications. ABSTRACT: Non-steroidal anti-inflammatory drugs (NSAIDs) express anti-tumoral activity mainly by blocking cyclooxygenase-2 involved in the synthesis of prostaglandins. Therefore, in the last few decades, many have attempted to explore the possibilities of applying this group of drugs as effective agents for the inhibition of neoplastic processes. This review summarizes the evidence presented in the literature regarding the anti-tumoral actions of NSAIDs used as monotherapies as well as in combination with conventional chemotherapeutics and natural products. In several clinical trials, it was proven that combinations of NSAIDs and chemotherapeutic drugs (CTDs) were able to obtain suitable results. The combination with phospholipids may resolve the adverse effects of NSAIDs and deliver derivatives with increased antitumor activity, whereas hybrids with terpenoids exhibit superior activity against their parent drugs or physical mixtures. Therefore, the application of NSAIDs in cancer therapy seems to be still an open chapter and requires deep and careful evaluation. The literature’s data indicate the possibilities of re-purposing anti-inflammatory drugs currently approved for cancer treatments.