Aspirin inhibits tumor progression and enhances cisplatin sensitivity in epithelial ovarian cancer

Abstract

Background Ovarian cancer is the most common gynecological malignancy and is difficult to manage due to the emergence of resistance to various chemotherapeutic drugs. New efforts are urgently awaited. Aspirin, which is traditionally considered a nonsteroidal anti-inflammatory drug (NSAID), has been reported to exert potential chemopreventive effects. Therefore, we aimed to investigate the anticancer effect and explore the underlying molecular mechanisms of aspirin on epithelial ovarian cancer (EOC) cells. Methods We conducted wound healing, transwell migration, EdU cell proliferation, colony formation and apoptosis detection assays to observe the effects of aspirin on the migration, proliferation and apoptosis of EOC cells (A2870, Caov-3, and SK-OV-3). EOC cells were treated with a combination of aspirin and cisplatin (CDDP) to observe the effect of aspirin on enhancing CDDP sensitivity. Orthotopic xenograft models of ovarian cancer established with A2780-Luciferase-GFP cells were applied to compare tumor growth inhibition in the control, CDDP and CDDP plus aspirin groups through in vivo imaging, which can be used to continuously monitor tumor growth. The expression and acetylation levels of p53 in EOC cells treated with aspirin were determined using western blotting, and p53 acetylation levels were examined in tumors harvested from the transplanted mice. Quantitative real-time PCR was used to assess the mRNA expression of p53 target genes. Results Aspirin inhibited migration and proliferation and induced apoptosis in EOC cell lines in a concentration-dependent manner. In vitro, aspirin enhanced the sensitivity of EOC cells to CDDP by increasing its inhibitory effect on proliferation and its effect on inducing apoptosis. In vivo, the differences in the tumor growth inhibition rates among the different CDDP experimental groups were statistically significant (p < 0.05). Aspirin did not affect p53 protein expression but increased the p53 acetylation level in a concentration-dependent manner. In addition, the mRNA levels of CDKN1A, BAX, FOXF1, PUMA, and RRAD in EOC cells were significantly increased by the aspirin treatment. Conclusions Aspirin inhibits tumor progression and enhances the CDDP sensitivity of EOC cells. These antitumor effects of aspirin might be mediated by p53 acetylation and subsequent activation of p53 target genes.

Aspirin Suppressed PD-L1 Expression through Suppressing KAT5 and Subsequently Inhibited PD-1 and PD-L1 Signaling to Attenuate OC Development

“…Aspirin inhibits EGF-stimulated viability of OC cells in a COX-1-dependent manner [ 18 ]. Aspirin promotes cisplatin sensitivity and represses tumor progression in epithelial OC [ 19 ]. Aspirin suppresses platelet-associated invasion of OC cells [ 20 ].…”

Pro-Inflammatory Signalling PRRopels Cisplatin-Induced Toxicity

“…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].…”

Looking at NSAIDs from a historical perspective and their current status in drug repurposing for cancer treatment and prevention

“…In addition, aspirin induced the expression of early apoptotic proteins such as caspase-3 and caspase-7 (Qorri et al 2020 ). Moreover, Guo et al ( 2021 ) examined the effects of aspirin treatment in epithelial ovarian cancer cell lines. In this study, aspirin exposure blocks tumor formation, proliferation, and migration through increasing expression of the acetylated and non-acetylated form of the p53 gene both in protein and mRNA levels in the A2780 epithelial ovarian cancer cells.…”

“…In this study, aspirin exposure blocks tumor formation, proliferation, and migration through increasing expression of the acetylated and non-acetylated form of the p53 gene both in protein and mRNA levels in the A2780 epithelial ovarian cancer cells. Besides, the expression of p53 target genes such as BAX, FOXF1, PUMA, RRAD were increased at the mRNA level (Guo et al 2021 ).…”