In clinical practice, aspirin (ASP) is widely used to reduce the risks of cardiovascular and cerebrovascular ischemia [24]. Numerous pharmacological, clinical, and epidemiological studies have demonstrated the protective effect of ASP against several types of cancer [25]. Cyclooxygenases (COX), the targets of NSAIDs, play a key role in homeostasis, inflammation, and immune modulation [26]. Increased expression of COX-1 and COX-2 has been observed in PC [27]. Additionally, increased production of thromboxane A2 (TXA2) and prostaglandins has been associated with the progression of PC [28]. COX-1 induces platelet aggregation and facilitates the adhesion of cancer cells to endothelial cells during metastasis [29,30]. COX-2 responds to inflammatory cytokines such as IL-1α, IL-1β, TNF-α, and lipopolysaccharide and produces increased amounts of prostaglandins in inflamed tissue. COX-2 also causes an increase in the expression of Bcl-2 in PC [18,31]. The inhibition of COX-1 and COX-2 are among the primary mechanisms through which ASP is thought to prevent cell growth [32]. ASP at low doses irreversibly inhibits COX-1 activity in platelets [33]. Inhibition of the COX-1/TXA2 pathway in platelets reduces platelet aggregation in tumor cells, endothelial activation, adhesion of tumor cells to endothelium, recruitment of metastasis-promoting monocytes/macrophages, and formation of the pre-metastatic niche in prostate tissue. High doses of ASP could inhibit COX-2 [30], resulting in the prevention of the production of prostanoids (TXA2, PGF2, PGE2, PGI2, and PGD2), which play a role in reducing apoptosis and increasing cell proliferation. It has been shown that PGE2 levels in human malignant PC tissues are 10 times higher than their levels in benign prostate tissues. PGE2 acts through receptors coupled with four G proteins named EP1, EP2, EP3, and EP4. EP3 has anti-tumor properties that can be induced by ASP. Therefore, it has been reported that ASP could exert its anti-PC properties through the activation of EP3 [34]. In another study, it was reported that ASP increased tumor necrosis factor-related ligand in PC cells by decreasing the expression of survivin, a member of the family of apoptosis-inhibiting proteins [32]. Studies have shown that ASP could inhibit the cell cycle by blocking cyclin-dependent kinases (CDKs) and causing cell cycle arrest in G0/G1 [35,36]. A retrospective case-control study demonstrated that treatment of PC cells with a combination of statin and ASP reduced both cyclin D1 expression and cell proliferation [35]. Regulatory T cells (Treg) prevent T cells from generating an effective antitumor response through immune system suppression [37,38]. A study examined the use of aspirin and statins in relation to inflammation in benign prostate tissue and revealed that aspirin could lead to a decrease in regulatory T cells [39]. COX-2/PGE2 inhibition has also been shown to reduce Treg cell activity in mouse lung cancer models [40]. In a cohort study analyzing 6594 men, ASP (low-dose < 300 mg, regular-strength 300–499 mg, extra-strength ≥ 500 mg) use was inversely associated with PC mortality [41]. Additionally, a prospective study reported that regular use of aspirin (325 mg, >3 d/wk for ≥1 yr) was associated with a reduction in the risk of lethal PC [42].

Ibuprofen (IBN), the most common NSAID, is typically administered to treat mild to moderate pain associated with a variety of conditions such as dysmenorrhea, headache, migraine, dental pain, and more [43]. IBN has also been reported to be effective in the prevention and treatment of certain cancers including colon, breast, lung, and gastric [44]. Several studies have been conducted to investigate the effects of IBN on PC. An in vitro study conducted in 2002 suggested that IBN had greater apoptotic and anti-proliferative effects on hormone-responsive cell lines (LNCaP and DU-145) compared to other NSAIDs including acetaminophen, ASP, naproxen, and NS-398 [45]. It was also reported that the anti-cancer effect of IBN treatment on PC3 and PC3 p53 +/+ cells was through cell cycle arrest at the G1/S stage, apoptosis induction via upregulation of caspase-3 and caspase-9, and inhibition of metastasis by upregulating E-cadherin [46].

2.3. Naproxen