Naringenin induces intrinsic and extrinsic apoptotic signaling pathways in cancer cells: A systematic review and meta-analysis of in vitro and in vivo data.

Various reports show the beneficial effect of naringenin on the development of cancer. We hypothesized that naringenin suppresses cancer cells by activating intrinsic and extrinsic apoptosis pathways. This systematic review and meta-analysis was performed to reveal the effect of naringenin on cancer inhibition in vitro and in vivo by altering apoptotic factors. Literature search was carried out using electronic databases including PubMed, Web of Science, Scopus, Google Scholar, and Embase up to February 2021. The heterogeneity test of the included studies was performed using the PRISMA checklist protocol and I2 statistic, respectively. Pooled standard mean difference and effect size (ES) with 95% confident interval (CI) were used to evaluate each relationship. A total of 32 articles were enrolled in our final analysis. Meta-analysis of the pooled findings for apoptosis, viability percentage, and apoptotic factors determined that treatment with naringenin affects viability and apoptosis in cancer cells in vitro and in vivo. Moreover, the results of in vitro experiments showed that naringenin increases the activity of caspase-3 (ES, 5.04; 95% CI, 2.61-7.47; I2 = 99.9), caspase-9 (ES, 2.99; 95% CI, 2.47-3.51; I2 = 93.7%), caspase-8 (ES, 2.86; 95% CI, 1.11-4.61; I2 = 99.7%), and Bax expression (ES, 2.73; 95% CI, 1.91-3.55; I2 = 99.4%) in cancer cells. It also increased the apoptotic rate and the activity of caspase-3 and caspase-9 in tumor-bearing animals. Overall, our findings highlight the potential therapeutic effects of naringenin in cancer inhibition through caspases cascade.