Abstract
Cancer is a major cause of death, affecting human life in both developed and developing countries. Numerous antitumor agents exist but their toxicity and low efficacy limits their utility. Furthermore, the complex pathophysiological mechanisms of cancer, serious side effects and poor prognosis restrict the administration of available cancer therapies. Thus, developing novel therapeutic agents are required towards a simultaneous targeting of major dysregulated signaling mediators in cancer etiology, while possessing lower side effects. In this line, the plant kingdom is introduced as a rich source of active phytochemicals. The secondary metabolites produced by plants could potentially regulate several dysregulated pathways in cancer. Among the secondary metabolites, flavonoids are hopeful phytochemicals with established biological activities and minimal side effects. Flavonoids inhibit B-cell lymphoma 2 (Bcl-2) via the p53 signaling pathway, which is a significant apoptotic target in many cancer types, hence suppressing a major dysregulated pathway in cancer. To date, there have been no studies reported which extensively highlight the role of flavonoids and especially the different classes of flavonoids in the modulation of Bcl-2 in the P53 signaling pathway. Herein, we discuss the modulation of Bcl-2 in the p53 signaling pathway by different classes of flavonoids and highlight different mechanisms through which this modulation can occur. This study will provide a rationale for the use of flavonoids against different cancers paving a new mechanistic-based approach to cancer therapy.
Highlights
Growing evidence has established a major role for B-cell lymphoma 2 (Bcl-2) through the p53 pathway in apoptosis and cancer phases [9,10,11]
Overexpression of the Bcl-2 gene is inherent to various cancers, for example, 90% of colorectal adenocarcinomas, 80% of undifferentiated nasopharyngeal cancers, 70% of breast adenocarcinomas and chronic lymphocytic leukaemias, 60% of gastric cancers, 30–60% of prostate cancers, and in varying percentages of melanomas, blastomas, and kidney cancers [94]
The isoliquiritigenin (Figure 5) have shown a significant anticancer effect through decreasing the production of prostaglandin E2 (PGE2) and nitric oxide (NO) in mice macrophages. This decrease in PGE2 was influenced by the downregulation of cyclooxygenase-2 expression, Bcl-2 and decreasing in NO which was influenced by the low expression of inducible nitric oxide synthase [114,115]
Summary
Flavonoids are natural compounds with promising biological activities and health benefits. These plant-derived secondary metabolites have been shown to target multiple dysregulated pathways in cancer [7,8]. Growing evidence has established a major role for B-cell lymphoma 2 (Bcl-2) through the p53 pathway in apoptosis and cancer phases [9,10,11]. Bcl-2 family will drive cell survival or death. Overexpression of the Bcl-2 protein has been reported in prostate cancer, breast cancer, B-cell lymphomas, and colorectal cancer [14]. Overexpression of the Bcl-2 protein promotes cell survival and proliferation. The current study is the first review regarding targeting Bcl-2 through the p53 pathway by flavonoids in cancer
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