Alkylating Agents

Gaté, Laurent; Tew, Kenneth D.

doi:10.1007/978-90-481-9704-0_4

Cited by 6 publications

(7 citation statements)

References 131 publications

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“…Hypo-or hyper-methylation of miRNA was considered to represent a new level of complexity in gene regulation in human cancers [81], suggesting miR-21 or miR-155 promoter hypo-methylation [81][82][83][84] and miR-422a hyper-methylation, as previously reported for miR-373 [81,85], as potential epigenetic modifications caused by tobacco carcinogenic effects on MMR. On the other hand, alkylating agents, such as NNK can also directly or after biological activation react and form covalent bonds with nucleophilic centers found in DNA and RNA and proteins [86], supporting possible direct interference of NNK with levels of miRNAs, thereby causing their deregulation [48,49,[51][52][53][54]. Subsequently, NNK-induced miRNA deregulations can affect MMR gene expression, either thought post-transcriptional modifications or through DNA methylation by targeting DNA methyltransferases or methylation-related proteins [81].…”

Section: Discussionmentioning

confidence: 99%

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells

Doukas

Vageli²,

Lazopoulos

et al. 2020

Cells

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Tobacco smoking is a common risk factor for lung cancer and head and neck cancer. Molecular changes such as deregulation of miRNA expression have been linked to tobacco smoking in both types of cancer. Dysfunction of the Mismatch DNA repair (MMR) mechanism has also been associated with a poor prognosis of these cancers, while a cross-talk between specific miRNAs and MMR genes has been previously proposed. We hypothesized that exposure of lung and head and neck squamous cancer cells (NCI and FaDu, respectively) to tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is capable of altering the expression of MSH2 and MLH1, key MMR components, by promoting specific miRNA deregulation. We found that either a low (1 µM) or high (2 µM) dose of NNK induced significant upregulation of "oncomirs" miR-21 and miR-155 and downregulation of "tumor suppressor" miR-422a, as well as the reduction of MMR protein and mRNA expression, in NCI and FaDu, compared to controls. Inhibition of miR-21 restored the NNK-induced reduced MSH2 phenotype in both NCI and FaDu, indicating that miR-21 might contribute to MSH2 regulation. Finally, NNK exposure increased NCI and FaDu survival, promoting cancer cell progression. We provide novel findings that deregulated miR-21, miR-155, and miR-422a and MMR gene expression patterns may be valuable biomarkers for lung and head and neck squamous cell cancer progression in smokers.Cells 2020, 9, 1031 2 of 22 and neck squamous cell carcinoma (HNSCC), represents one of the most aggressive malignancies with a high rate of mortality. [8,9]. Tobacco smoking has been one of the most well-established risk factors for both lung and head and neck cancers [1][2][3][4][5][6][7][8]. It is known that tobacco smoke contains a mixture of thousands of compounds, including a large number of known carcinogens [2]. It is believed that exposure of cells to tobacco smoke carcinogens can lead to DNA damage, which may cause chromosomal instability and increased cell proliferation [10][11][12][13]. In particular, tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is one of the chemicals in tobacco smoke, has been linked to lung and head and neck cancer [14], and has also been shown to upregulate oncogenic pathways [15][16][17].The development and progression of lung and head and neck malignancies appear to be a complex process. Although multiple diagnostic and prognostic markers have been identified for both lung and head and neck cancers [18,19], the precise molecular mechanisms involved in the development and progression of these malignancies remain unclear.We understand that a functional DNA repair mechanism that includes the recognition and repair of mismatch DNA errors during DNA replication is essential in eliminating the harmful effect of several environmental risk factors, such as NNK, on the exposed cells [20][21][22][23]. A number of studies have shown that reduced expression of mismatch DNA repair (MMR) genes increases the incidence of microsatellite ...

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Section: Discussionmentioning

confidence: 99%

The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells

Doukas

Vageli²,

Lazopoulos

et al. 2020

Cells

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“…2). The nitrogen mustards and aziridine compounds are two major classes of bifunctional alkylating drugs used for cancer treatment that can crosslink DNA through a aziridinium-ring intermediate 12 . Nitrogen mustard compounds react readily with N7-guanine and to a lesser extent, N3- and N7-adenine, to form bulky N-monoadducts.…”

Section: Molecular Damage Caused By Alkylating Agentsmentioning

confidence: 99%

Balancing repair and tolerance of DNA damage caused by alkylating agents

2012

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Alkylating agents comprise a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER), and mismatch repair (MMR) respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for an organism's favorable response to alkylating agents. Furthermore, an individual's response to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity.

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“…Alkylating agents were the first generation of anticancer agents that had been shown to be effective against squamous cell carcinoma. 11 The first alkylating agent used in clinical treatment was ifosfamide, in the early 1970s. Then, many alkylating agents were gradually introduced to China from the late 1970s, including cyclophosphamide and chlorambucil.…”

Section: Resultsmentioning

confidence: 99%

“…Folate antagonists, or antifolates, are cytotoxic drugs that have been extensively used for a range of diseases. 11 Also, the folate antagonists were induced to China in the 1940s as the earliest subclass. Since folate is needed for DNA synthesis and repair, rapidly dividing cells such as hematopoietic cells and those found in the gastrointestinal tract are most affected.…”

Section: Resultsmentioning

confidence: 99%