Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach

Abstract

Cancer is, globally, one of the main causes of death. Even though various therapies are available, they are still painful because of their adverse side effects. Available treatments frequently fail due to unpromising responses, resistance to classical anticancer drugs, radiation therapy, chemotherapy, and low accessibility to tumor tissues. Developing novel strategies to minimize adverse side effects, improve chemotherapy sensitivity, and control cancer progression is needed. Many studies have suggested small dietary molecules as complementary treatments for cancer patients. Different components of herbal/edible plants, known as flavonoids, have recently garnered attention due to their broad biological properties (e.g., antioxidant, antiviral, antimicrobial, anti-inflammatory, anti-mutagenic, anticancer, hepatoprotective, and cardioprotective). These flavonoids have shown anticancer activity by affecting different signaling cascades. This article summarizes the key progress made in this area and discusses the role of flavonoids by specifically inhibiting the PI3K/Akt/mTOR pathway in various cancers.

Keywords: Akt; PI3K; cancer; flavonoids; inhibitors; mTOR.

Figure 1

Common flavonoids from dietary sources, with their biological activities. EGCG; Epigallocatechin gallate. (Source: The effects of polyphenols and other bioactives on human health. https://pubs.rsc.org/image/article/2019/fo/c8fo01997e/c8fo01997e-f1_hi-res.gif accessed on 29 October 2021).

Figure 2

PI3K/Akt signaling pathway; PIP2, phosphatidylinositol 4, 5-bisphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PDK1, 3-phosphoinositide-dependent kinase 1; PP2A, protein phosphatase 2A; BAD, BCL2 associated agonist of cell death; GLUT4, glucose transporter type 4; GPCRs, G-protein-coupled receptors; TSC, tuberous sclerosis complex; FOXO1, forkhead box O1 protein; NO, nitric oxide.

Figure 3

mTOR signaling cascade; IGF-1, insulin-like growth factor 1; EGF, epidermal growth factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; PIP2, phosphatidylinositol 4, 5-bisphosphate; PDK1, 3-phosphoinositide-dependent kinase 1; TSC1/2, tuberous sclerosis complex 1/2; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; eIF4E, eukaryotic translation initiation factor 4E; PTEN, phosphatase and tensin homolog deleted on chromosome 10; IRS1, insulin receptor substrate 1; 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; p70S6K1, p70 ribosomal S6 kinase 1; Rheb GDP, Ras homolog enriched in brain GDP; Rheb GTP, Ras homolog enriched in brain GTP.