Salicylate, the prototype of NSAIDs, has shown promising anticancer effects [36,37,38]. Several studies indicated that salicylate can, by different mechanisms, increase the cytotoxic efficacy of CDDP. In one study, salicylate was reported to improve the anti-tumor effects of CDDP against T cell lymphoma via changing the tumor microenvironment pH, altering the expression of the cell cycle’s regulatory/apoptotic factors, such as p53, bcl-2, bcl-xL, cyclin B1, and D, as well as cytokines IFN-γ, VEGF, IL-4, and -10 [39]. Other studies showed that salicylate also increased the anti-tumor effect of CDDP against osteosarcoma, through modulating the NF-κB pathway [40], and against non-small cell lung carcinoma stem-like cells by repressing migration through acting on the mTOR-Akt axis [41]. In addition, salicylate improved CDDP toxicity against colon cancer cells through preventing NF-κB binding to a COX-2 promoter [42] against lung cancer cells, by abrogating cancer cell stemness [43], against epithelial ovarian cancer cells by increasing p53 acetylation and promoting apoptosis [44], and against oesophageal squamous cell carcinoma through epigenetic modulation of chromatin by altering histone acetylation levels [45]. Due to these beneficial effects, asplatin or prodrug platin-A, which are CDDP-based Pt(IV) prodrugs complexed with salicylate, were developed to improve cytotoxicity against resistant cancer cells [46,47]. Despite its obvious potentiating cytotoxic effects on tumor cells, salicylate might have a protective effect on normal cells against CDDP-induced nephrotoxicity, ototoxicity, and neurotoxicity [48,49,50].

Ibuprofen, one of the propionic acid-derived NSAIDs, showed cytotoxic effects when administered alone to human promyelocytic leukemia and colon carcinoma cells [51]. Some studies succeeded in synthesizing lipid encapsulated ibuprofen metallodrug nanoparticles to overcome CDDP chemoresistance in glioblastoma cancer cells [52]. It was also reported that ibuprofen increased CDDP anticancer efficacy against lung cancer cells through depletion of heat shock protein 70, thus enhancing tumor cell apoptosis [53]. In addition, combining ibuprofen with CDDP caused a higher cytotoxic effect on thyroid and pancreatic cancer cells in vitro [54]. Furthermore, an ibuprofen/CDDP combination reversed CDDP resistance in non-small-cell lung cancer through a COX-independent mechanism [55]. In addition to increasing CDDP’s cytotoxic efficacy, ibuprofen was reported to inhibit human ovarian cancer cell metastasis into several organs, such as the liver, lungs, bone marrow, and spleen in mice [56]. Unfortunately, through stimulating oxidative stress, ibuprofen might cause toxicity similar to CDDP on the kidneys and liver [57,58].

Ketoprofen, another propionic acid-derived NSAID, was conjugated with CDDP-based Pt(IV) prodrug to form ketoplatin that could delay breast cancer cells’ tumor growth and had less systemic toxic effects compared to CDDP alone in vitro and in vivo [59]. Interestingly, ketoprofen was suggested to protect against CDDP-induced nephrotoxicity [60], which is in line with more recent findings that ketoprofen has no nephrotoxic effects [61]. Several trials were also performed to assess the anti-tumor effects of combining CDDP with a third propionic acid-derived NSAID, naproxen [62,63], where the combination showed higher cytoxicity than CDDP alone on human cancer cells of the lungs and ovaries, with less toxicity on normal human liver cells [64]. Similar results were shown for a naproxen/CDDP combination on triple-negative breast cancer [65], as well as on ovarian endometrioid adenocarcinoma, lung adenocarcinoma, malignant pleural mesothelioma, and colon carcinoma cells [28]. Carprofen alone was able to ameliorate canine osteosarcoma in vitro [66]. Novel NSAIDs were created, such as derivatives of naproxen, flurbiprofen, and ibuprofen, that showed promising anticancer effect against cultured human glioblastoma cells [67], as well as human liver, breast, and colon carcinoma cells [68]. Whether the anticancer effects of these NSAIDS would be additive to that of CDDP or not still needs further investigation.

One of the acetic acid-derived NSAIDs, indomethacin, attenuated the growth of human oesophageal squamous carcinoma cells [69]. Sulindac could also ameliorate the growth rate of oral tumor cells and help their elimination by natural killer cells [70]. In addition, sulindac could prevent the progression of colorectal cancer clinically, by up-regulating cyclin G2 which resulted in delaying tumor cell cycle progression [71]. Interestingly, sulindac showed comparable cytotoxic effects to those of CDDP when tested on HEK293 cells [72]. Given together with CDDP, ketorolac succeeded in reversing CDDP chemo-resistance in a patient-derived cell xenograft model [73]. Diclofenac also showed improved CDDP anticancer effects against human lung adenocarcinoma CDDP-resistant cells [74,75]. To the contrary to what is expected from non-selective COX inhibitors, diclofenac did not deteriorate CDDP-induced nephrotoxicity [74]. Nevertheless, diclofenac, as with CDDP, had the hazard of causing hepatotoxicity as an adverse effect [76].

Meloxicam, an enolic acid derivative of NSAIDs with relative preferential selectivity to inhibit COX-2, had a synergistic effect on CDDP cytotoxicity in human osteosarcoma cells [77]. Interestingly, meloxicam protected the kidney from CDDP-induced renal lesions in mice [78]. Oxicams have been suggested as chemosensitizers of CDDP, and some trials attempted to develop CDDP–oxicam complexes as anticancer drugs, using meloxicam and isoxicam, where the results showed promising cytotoxic effects on different cell lines in vitro [79]. Piroxicam, another enolic acid derivative of NSAIDs, when given as an adjuvant to CDDP-loaded nanoparticles, increased apoptosis in mesothelioma cells [80]. Unfortunately, unlike meloxicam, piroxicam was shown to worsen CDDP-induced nephrotoxicity in rats [81]. Tenoxicam alone seemed tolerable in patients with renal impairment [82], but was reported to have an injurious effect on the liver [83].

The anthranilic acid derivatives, flufenamic and mefenamic acids, were reported to augment CDDP’s anticancer effect in vitro through inhibiting aldo–keto reductase 1C enzyme [84,85]. Similarly, tolfenamic acid was coupled with CDDP to form a nanoprodrug that had tumor apoptotic and anti-metastatic effects on breast cancer in vitro and in vivo [26]. On their own, neither meclofenamic nor niflumic acid showed promising anticancer effects against uterine cervical cancer and breast adenocarcinoma cells, respectively [86,87]. Concerning safety, meclofenamic acid could aggravate CDDP-induced renal damage [88]. However, meclofenamic acid seemed to have the potential to protect against CDDP-induced ototoxicity via improving the viability of ear hair cells [89]. Nabumetone, a naphthylalanine derivative, had an antiproliferative effect on MCF-7 and MDA-MB-231 breast carcinoma cells [90], with low toxic effects on gastric mucosa cells [91].

Selective COX-2 inhibitors, frequently referred to as “coxibs”, were reported to have, on their own, promising potential for preventing and treating malignancies [92,93]. Administered with CDDP, rofecoxib was reported to enhance cytotoxic effects on gastric cancer cells by down regulating multidrug resistance protein 1 expression [94]. Nevertheless, combining CDDP with celecoxib did not improve the anticancer activity of CDDP against human esophageal squamous cell carcinoma xenograft model in vivo [95]. Despite their safety with regards to gastric ulceration, selective COX-2 inhibitors were reported to mediate cardiotoxicity [32]. Indeed, several members of this group, such as valdecoxib and rofecoxib, were removed from the market due to their potential cardiovascular hazards [96,97]. Despite its reported hazard on cardiomyocytes [98], celecoxib only received a box warning on its pack, but is still sold in the market. Interestingly, parecoxib was reported to have a protective effect on ischemia-reperfusion injury of the heart in rats [99]. Celecoxib showed protective effect against CDDP-induced nephrotoxicity [100]. Another coxib, still present on the market, etoricoxib, was tested for possible nephroprotective effects against CDDP-induced renal toxicity in rats, but, unfortunately, the results were not conclusive [101].