Aspirin inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo via inducing cell cycle arrest and apoptosis

Abstract

Aspirin, a nonsteroidal anti-inflammatory drug (NSAID), is known to inhibit cell proliferation in a variety of cancers. However, the underlying mechanism of this inhibition remains unknown. We investigated the effects of aspirin on hepatocellular carcinoma (HCC) cells using in vitro and in vivo models. Six HCC cell lines and a liver cancer cell line including Huh-7 were used in assays that evaluated cell proliferation, cell cycle, and apoptosis. Flow cytometry, enzyme-linked immunosorbent assay (ELISA), western blot analysis, and phosphorylated receptor tyrosine kinase array were used to evaluate the effects of aspirin on the cells, and microRNAs (miRNAs) were analyzed by a miRNA array chip. The results were validated in vivo using a nude mouse model of Huh-7-xenografted tumors. Our results showed that aspirin exhibited an antiproliferative effect on all cell lines. Moreover, aspirin induced G 0 /G 1 cell cycle arrest and modulated the levels of cell cycle-related molecules such as cyclin E, cyclin D1, and cyclin-dependent kinase 2 (Cdk2). In addition, aspirin upregulated the levels of caspase-cleaved cytokeratin 18, increased the proportion of early apoptotic cells, decreased the levels of clusterin and heat shock protein 70 (HSP 70), upregulated the levels of miRNA-137 and inhibited epidermal growth factor receptor (EGFR) activation. In addition, we observed that aspirin suppressed cell proliferation partially through the miRNA-137/EGFR pathway. Our in vivo results showed that aspirin reduced the growth of xenograft tumors in nude mice. In conclusion, aspirin was able to inhibit the growth of HCC cells by cell cycle arrest, apoptosis, and alteration of miRNA levels in in vitro and in vivo models.

A novel role for aspirin in enhancing the reprogramming function of miR‐302/367 cluster and breast tumor suppression

“…EMT, epithelial-mesenchymal transition; mRNA, messenger RNA apoptosis in cancer cells, including breast cancer cells. 25,[52][53][54][55] ASA induces BC cell apoptosis through regulation of BAX/BCL-2 and caspase-3 expression. 25 Another study showed that ASA targets BCL-2 in MCF-7 cells leading to inhibition of cell proliferation and enhanced apoptotic rate of these cells.…”

“…In regard to the apoptotic rate, while ectopic expression of the miR‐302/367 cluster increased the early apoptotic rate of both cell lines, ASA treatment caused a significant enhancement of the miR‐302/467 effect. ASA has been shown to induce apoptosis in cancer cells, including breast cancer cells 25,52–55 . ASA induces BC cell apoptosis through regulation of BAX/BCL‐2 and caspase‐3 expression 25 .…”

Breast Cancer Drug Repurposing a Tool for a Challenging Disease

“…There are compelling evidences authenticating that regular use of low doses of aspirin results in a significant reduction in the occurrences and mortality of various cancers [13][14][15][16][17]. The Drug Repurposing -Molecular Aspects and Therapeutic Applications possibility that Aspirin has an anticancer benefit has received considerable interest nowadays, with a lot of research being done to figure out how successful it is in the prevention of colorectal cancer [18], lung cancer [19], gastric cancer [20], prostate cancer [21], and many other cancers including breast cancer. Because of the effect of Aspirin in several biological processes such as inhibitory effect on angiogenesis [22], cancer cell metastasis [23], causing cell apoptosis [24], etc., it is reasonable to predict that Aspirin will be beneficial when employed as an additional alternative treatment option for cancer patients.…”

Aspirin-Based Organoiron Dendrimers as Promising Anti-Inflammatory, Anticancer, and Antimicrobial Drugs

“…Recent studies on COX-1 and COX-2 inhibitors are focused on increasing the selectivity index of drugs towards COX-1 and COX-2 as it acts as the main effector in the mech- It has been demonstrated that aspirin inhibits the human HCC cells and tumor cells by suppressing cell cycle-related molecules and inducing cell apoptosis by increasing oxidative stress [80,81]. Recent analysis has indicated that there was a significant inverse association between aspirin dose and cell proliferation [81,82]. As shown in Figure 9, G3-D9-Asp inhibited the cell proliferation in a concentration-dependent manner.…”