NSAIDs: Old Acquaintance in the Pipeline for Cancer Treatment and Prevention─Structural Modulation, Mechanisms of Action, and Bright Future

Abstract

The limitations of current chemotherapeutic drugs are still a major issue in cancer treatment. Thus, targeted multimodal therapeutic approaches need to be strategically developed to successfully control tumor growth and prevent metastatic burden. Inflammation has long been recognized as a hallmark of cancer and plays a key role in the tumorigenesis and progression of the disease. Several epidemiological, clinical, and preclinical studies have shown that traditional nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit anticancer activities. This Perspective reports the most recent outcomes for the treatment and prevention of different types of cancers for several NSAIDs alone or in combination with current chemotherapeutic drugs. Furthermore, an extensive review of the most promising structural modifications is reported, such as phospho, H2S, and NO releasing-, selenium-, metal complex-, and natural product-NSAIDs, among others. We also provide a perspective about the new strategies used to obtain more efficient NSAID- or NSAID derivative- formulations for targeted delivery.

Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents

“…NSAIDs are well recognised as inhibitors of the COX enzymes, COX-1 and COX-2 [37,42,45]. While both COX-1 and COX-2 are responsible in prostaglandin production, they are distinct from one another in terms of their tissue distribution and regulation of gene expression [49,105].…”

“…In particular, the coordination of non-steroidal anti-inflammatory drugs (NSAIDs) to the cores of cisplatin and its derivatives have resulted in chemo-anti-inflammatory prodrugs that are capable of reversing chemoresistance because of enhanced bioavailability [37][38][39][40][41]. Since the 1970s, NSAIDs have been extensively administered to cancer patients, simply for cancer pain management, but there was also a growing curiosity as to whether the regular ingestion of NSAIDs would help combat cancer and decrease cancer risk [42][43][44][45]. NSAIDs suppress The configurational arrangement of platinum(IV) complexes is an attribute of the design and a game changer for researchers in this area of research.…”

Pro-Inflammatory Signalling PRRopels Cisplatin-Induced Toxicity

“…Unlike those therapeutics, however, meta-analyses have identified cases wherein NSAIDs have, unexpectedly, resulted in either the inhibition of cisplatin treatment or the promotion of CITs-CINs and CICs specifically [311]. Despite this, research into NSAID use during chemotherapy has continued, and several NSAIDs appear capable of improving the outcomes of cisplatin chemotherapy in-vitro and in-vivo [312]. Etoricoxib, as described above, qualifies as a typical NSAID and is representative, in truth, of quite a number of NSAIDs, such as the salicylates, with demonstrable capacity to alleviate CITs, such as CIO and CIN, with little to negative effects on chemotherapy.…”

“…There are reports of salicylates selectively boosting the cytotoxicity of cisplatin against tumours as chemosensitisers as well [313][314][315][316]. Indeed, there are numerous studies that suggest that anti-inflammatory approaches, even beyond the use of NSAIDs, may actually improve the outcomes of chemotherapy [312,[317][318][319][320][321]. More importantly, literature detailing the potential of aforementioned compounds (Tables 1 and 3) as chemosensitisers for chemotherapy-cisplatin included-is growing likely extensively enough to warrant its own review [322][323][324][325][326][327].…”

Nickel‐Catalyzed Enantioconvergent Carboxylation Enabled by a Chiral 2,2′‐Bipyridine Ligand

“…In particular, 2‐arylpropionic acid is the key common backbone found in the profen family of nonsteroidal anti‐inflammatory drugs (NSAIDs) such as ( S )‐naproxen, ( S )‐indoprofen and ( S )‐clidanac (Figure 1). [1c, d] Moreover, α‐chiral aryl acetic acids and derivatives are present in diverse families of natural products such as the alkaloid anticholinergic drug scopolamine, [1e, f] polyphenolic antioxidant salvianolic acid B [1g] and sesquiterpene antimalaria drug artemisinin (Qinghaosu) [1h] . Therefore, development of new and efficient approaches to α‐chiral carboxylic acids has continuously been attractive for synthetic chemists [2]…”