Activation and Inhibition of ATM by Phytochemicals: Awakening and Sleeping the Guardian Angel Naturally

Abstract

Double-stranded breaks (DSBs) are cytotoxic DNA lesions caused by oxygen radicals, ionizing radiation, and radiomimetic chemicals. Increasing understanding of DNA damage signaling has provided an ever-expanding list of modulators reported to orchestrate DNA damage repair and ataxia telangiectasia mutated (ATM) is the master regulator and main transducer of the DSB response. Increasingly, it is being realized that DNA damage response is a synchronized and branched network that functionalizes different molecular cascades to activate special checkpoints, thus temporarily arresting progression of the cell cycle while damage is being assessed and processed. It is noteworthy that both nutrigenetics and nutrigenomics have revolutionized the field of molecular biology and rapidly accumulating experimental evidence has started to shed light on biological activities of a wide range of phytochemicals reported to modulate cell cycle, DNA repair, cell growth, differentiation and apoptosis as evidenced by cell-based studies. In this review, we have attempted to provide an overview of DNA damage signaling, how ATM signaling regulates tumor necrosis factors-related apoptosis inducing ligand (TRAIL)-induced intracellular network. We also illuminate on how resveratrol, epigallocatechin gallate, curcumin, jaceosidin, cucurbitacin, apigenin, genistein, and others trigger activation of ATM in different cancer cells as well as agents for ATM inactivation. Understanding the interplay of TRAIL-induced intracellular signaling and ATM modulation of downstream effectors is very important. This holds particularly for a reconceptualization of the apparently paradoxical roles and therapeutically targetable for enhancing the response to DNA damage-inducing therapy.

Apigenin inhibits renal cell carcinoma cell proliferation

“…As a natural phytoestrogen flavonoid widely distributed in vegetables and fruits [1], apigenin (4′,5,7-trihydroxyflavone) effectively inhibits proliferation in multiple cancer cell types, including colon, lung, breast, prostate, melanoma, and leukemia [2–7] and DNA damage mechanisms were comprised in lots of studies [8]. Apigenin may also exhibit reduced systemic toxicity compared to other flavonoids [9].…”

Critical roles of Rad54 in tolerance to apigenin‑induced Top1‑mediated DNA damage

“…In addition, APG was demonstrated to induce reactive oxygen species and p38, which are essential substances in the process of cell death (7,13,14). Furthermore, it was observed that APG induced DNA lesions involving DNA breaks (15), micronuclei, chromosomal aberrations (CAs) and chromatid exchanges (16)(17)(18). APG was further demonstrated to have significant topoisomerase I (Top1) inhibitor activities (19).…”

Differential Methylation and Acetylation as the Epigenetic Basis of Resveratrol’s Anticancer Activity

“…The realization of the potent anticancer properties of resveratrol was followed by numerous investigations into the various signaling pathways that it affects, leading to the observed effects [12,13,14,15,16,17]. In recent years, the focus of cancer research has shifted to stem cells, epithelial-to-mesenchymal transition (EMT) and epigenetic regulation, even in the context of lead compounds such as resveratrol that have a natural origin.…”