Unboxing the molecular modalities of mutagens in cancer

Abstract

Graphical abstract The etiology of the majority of human cancers is associated with a myriad of environmental causes, including physical, chemical, and biological factors. DNA damage induced by such mutagens is the initial step in the process of carcinogenesis resulting in the accumulation of mutations. Mutational events are considered the major triggers for introducing genetic and epigenetic insults such as DNA crosslinks, single- and double-strand DNA breaks, formation of DNA adducts, mismatched bases, modification in histones, DNA methylation, and microRNA alterations. However, DNA repair mechanisms are devoted to protect the DNA to ensure genetic stability, any aberrations in these calibrated mechanisms provoke cancer occurrence. Comprehensive knowledge of the type of mutagens and carcinogens and the influence of these agents in DNA damage and cancer induction is crucial to develop rational anticancer strategies. This review delineated the molecular mechanism of DNA damage and the repair pathways to provide a deep understanding of the molecular basis of mutagenicity and carcinogenicity. A relationship between DNA adduct formation and cancer incidence has also been summarized. The mechanistic basis of inflammatory response and oxidative damage triggered by mutagens in tumorigenesis has also been highlighted. We elucidated the interesting interplay between DNA damage response and immune system mechanisms. We addressed the current understanding of DNA repair targeted therapies and DNA damaging chemotherapeutic agents for cancer treatment and discussed how antiviral agents, anti-inflammatory drugs, and immunotherapeutic agents combined with traditional approaches lay the foundations for future cancer therapies.

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

“…Patients with a co-mutation in multiple DDR pathways demonstrate a good response to ICIs [59,74]. HRR-MMR, or co-mutation in the HRR-BER pathway, is regarded as a potential biomarker [74][75][76]. In a study on pembrolizumab, 11 of 34 non-small cell lung cancer (NSCLC) patients were assigned to the co-mutation positive (co-mut+) group [74], in which ORR was 63.6% compared with 21.7% of the co-mutation negative (co-mut-) group.…”

Case Report: Malignant Melanoma Associated With COVID-19: A Coincidence or a Clue?

“…Epidemiological studies suggest that chronic inflammation may be linked to 15–20% of cancer deaths worldwide ( 30 , 31 ). Hence, the concept that virus-induced inflammation promotes tumorigenesis is not novel.…”

Apigeninidin-enriched Sorghum bicolor (L. Moench) extracts alleviate Aflatoxin B1-induced dysregulation of male rat hypothalamic-reproductive axis

“…7 AFBO is a highly reactive and unstable AFB 1 metabolite that reacts with cellular macromolecules, including genetic materials-DNA, RNA, proteins, and membrane lipids, mediating lipid peroxidation (LPO) and cell damage. 8 Primarily, AFB 1 is hepatotoxic, yet, AFB 1 equally affects the reproductive system. Prior animal studies have revealed that sublethal doses of AFB 1 cause testicular degeneration.…”

“…7 AFBO is a highly reactive and unstable AFB 1 metabolite that reacts with cellular macromolecules, including genetic materials—DNA, RNA, proteins, and membrane lipids, mediating lipid peroxidation (LPO) and cell damage. 8…”