Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy

2003 ◽  
Vol 31 (6) ◽  
pp. 1372-1377 ◽  
Author(s):  
P.J. Thornalley
Keyword(s):  
Drug Resistance ◽  
Excision Repair ◽  
Glyoxalase I ◽  
Drug Induced ◽  
Antitumour Agents ◽  
Lung Carcinoma Cells ◽  
Antitumour Agent ◽  
A Cell ◽  
Base Excision ◽  
Induced Apoptosis

Glycation of nucleotides in DNA forms AGEs (advanced glycation end-products). Nucleotide AGEs are: the imidazopurinone derivative dG-G {3-(2´-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin-9(8)one}, CMdG (N2-carboxymethyldeoxyguanosine) and gdC (5-glycolyldeoxycytidine) derived from glyoxal, dG-MG {6,7-dihydro-6,7-dihydroxy-6-methylimidazo-[2,3-b]purine-9(8)one}, dG-MG2 [N2,7-bis-(1-hydroxy-2-oxopropyl)deoxyguanosine] and CEdG [N2-(1-carboxyethyl)deoxyguanosine] derived from methylglyoxal, and dG-3DG [N2-(1-oxo-2,4,5,6-tetrahydroxyhexyl)deoxyguanosine] derived from 3-deoxyglucosone and others. Glyoxal and methylglyoxal induce multi-base deletions, and base-pair substitutions – mostly occurring at G:C sites with G:C→C:G and G:C→T:A transversions. Suppression of nucleotide glycation by glyoxalase I and aldehyde reductases and dehydrogenases, and base excision repair, protects and recovers DNA from damaging glycation. The effects of DNA glycation may be most marked in diabetes and uraemia. Mutations arising from DNA glycation may explain the link of non-dietary carbohydrate intake to incidence of colorectal cancer. Overexpression of glyoxalase I was found in drug-resistant tumour cells and may be an example of an undesirable effect of the enzymatic protection against DNA glycation. Experimental overexpression of glyoxalase I conferred resistance to drug-induced apoptosis. Glyoxalase I-mediated drug resistance was found in human leukaemia and lung carcinoma cells. Methylglyoxal-mediated glycation of DNA may contribute to the cytotoxicity of some antitumour agents as a consequence of depletion of NAD+ by poly(ADP-ribose) polymerase, marked increases in triosephosphate concentration and increased formation of methylglyoxal. S-p-Bromobenzylglutathione cyclopentyl diester is a cell-permeable glyoxalase I inhibitor. It countered drug resistance and was a potent antitumour agent against lung and prostate carcinoma. Glyoxalase I overexpression was also found in invasive ovarian cancer and breast cancer.

Base excision repair pathways of bacteria: new promise for an old problem

2020 ◽  
Vol 12 (4) ◽  
pp. 339-355 ◽  
Author(s):  
Krishna Kurthkoti ◽  
Pradeep Kumar ◽  
Pau Biak Sang ◽  
Umesh Varshney
Keyword(s):  
Immune Response ◽  
Drug Resistance ◽  
Small Molecules ◽  
Base Excision Repair ◽  
Drug Target ◽  
Excision Repair ◽  
Genomic Integrity ◽  
Repair Pathways ◽  
Cellular Pathways ◽  
Base Excision

Infectious diseases continue to be a major cause of human mortality. With the emergence of drug resistance, diseases that were long thought to have been curable by antibiotics are resurging. There is an urgent clinical need for newer antibiotics that target novel cellular pathways to overcome resistance to currently used therapeutics. The base excision repair (BER) pathways of the pathogen restore altered bases and safeguard the genomic integrity of the pathogen from the host's immune response. Although the BER machinery is of paramount importance to the survival of the pathogens, its potential as a drug target is largely unexplored. In this review, we discuss the importance of BER in different pathogenic organisms and the potential of its inhibition with small molecules.

scholarly journals Ion channels and transporters in the development of drug resistance in cancer cells

2014 ◽  
Vol 369 (1638) ◽  
pp. 20130109 ◽  
Author(s):  
Else K. Hoffmann ◽  
Ian H. Lambert
Keyword(s):  
Drug Resistance ◽  
Ion Channels ◽  
Drug Uptake ◽  
Multi Drug Resistance ◽  
Drug Efflux ◽  
Ion Transporters ◽  
Drug Induced ◽  
And Migration ◽  
Induced Apoptosis ◽  
Proliferation And Migration

Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of ion transporters is the main focus of this paper and we demonstrate how pro-apoptotic ion channels are downregulated, while anti-apoptotic ion transporters are upregulated in MDR. We also discuss whether upregulation of ion transport proteins that are important for proliferation contribute to MDR. Finally, we discuss the possibility that the development of MDR involves sequential and localized upregulation of ion channels involved in proliferation and migration and a concomitant global and persistent downregulation of ion channels involved in apoptosis.

scholarly journals Development of a Cell-Based Assay for Measuring Base Excision Repair Responses

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Tyler Golato ◽  
Boris Brenerman ◽  
Daniel R. McNeill ◽  
Jianfeng Li ◽  
Robert W. Sobol ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
A Cell ◽  
Base Excision ◽  
Measuring Base

scholarly journals Overexpression of caspase-3 restores sensitivity for drug-induced apoptosis in breast cancer cell lines with acquired drug resistance

Oncogene ◽  
2001 ◽  
Vol 20 (22) ◽  
pp. 2749-2760 ◽  
Author(s):  
Katrin Friedrich ◽  
Thomas Wieder ◽  
Clarissa Von Haefen ◽  
Silke Radetzki ◽  
Reiner Jänicke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Caspase 3 ◽  
Breast Cancer Cell Lines ◽  
Drug Induced ◽  
Acquired Drug Resistance ◽  
Induced Apoptosis

scholarly journals Full-length p73α Represses Drug-induced Apoptosis in Small Cell Lung Carcinoma Cells

2005 ◽  
Vol 280 (40) ◽  
pp. 34159-34169 ◽  
Author(s):  
Ulrika Nyman ◽  
Agnieszka Sobczak-Pluta ◽  
Pinelopi Vlachos ◽  
Thomas Perlmann ◽  
Boris Zhivotovsky ◽  
...  
Keyword(s):  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Carcinoma Cells ◽  
Full Length ◽  
Small Cell Lung ◽  
Drug Induced ◽  
Cell Lung Carcinoma ◽  
Lung Carcinoma Cells ◽  
Induced Apoptosis

scholarly journals A Novel Role for the DNA Repair Enzyme 8-Oxoguanine DNA Glycosylase in Adipogenesis

2021 ◽  
Vol 22 (3) ◽  
pp. 1152
Author(s):  
Sai Santosh Babu Komakula ◽  
Bhavya Blaze ◽  
Hong Ye ◽  
Agnieszka Dobrzyn ◽  
Harini Sampath
Keyword(s):  
Adipocyte Differentiation ◽  
Excision Repair ◽  
Adipogenic Differentiation ◽  
Weight Maintenance ◽  
Transgenic Animals ◽  
Dna Glycosylase ◽  
Antioxidant Defenses ◽  
Dna Glycosylases ◽  
A Cell ◽  
Base Excision

Cells sustain constant oxidative stress from both exogenous and endogenous sources. When unmitigated by antioxidant defenses, reactive oxygen species damage cellular macromolecules, including DNA. Oxidative lesions in both nuclear and mitochondrial DNA are repaired via the base excision repair (BER) pathway, initiated by DNA glycosylases. We have previously demonstrated that the BER glycosylase 8-oxoguanine DNA glycosylase (OGG1) plays a novel role in body weight maintenance and regulation of adiposity. Specifically, mice lacking OGG1 (Ogg1−/−) are prone to increased fat accumulation with age and consumption of hypercaloric diets. Conversely, transgenic animals with mitochondrially-targeted overexpression of OGG1 (Ogg1Tg) are resistant to age- and diet-induced obesity. Given these phenotypes of altered adiposity in the context of OGG1 genotype, we sought to determine if OGG1 plays a cell-intrinsic role in adipocyte maturation and lipid accumulation. Here, we report that preadipocytes from Ogg1−/− mice differentiate more efficiently and accumulate more lipids than those from wild-type animals. Conversely, OGG1 overexpression significantly blunts adipogenic differentiation and lipid accretion in both pre-adipocytes from Ogg1Tg mice, as well as in 3T3-L1 cells with adenovirus-mediated OGG1 overexpression. Mechanistically, changes in adipogenesis are accompanied by significant alterations in cellular PARylation, corresponding with OGG1 genotype. Specifically, deletion of OGG1 reduces protein PARylation, concomitant with increased adipogenic differentiation, while OGG1 overexpression significantly increases PARylation and blunts adipogenesis. Collectively, these data indicate a novel role for OGG1 in modulating adipocyte differentiation and lipid accretion. These findings have important implications to our knowledge of the fundamental process of adipocyte differentiation, as well as to our understanding of lipid-related diseases such as obesity.

scholarly journals A recent development of new therapeutic agents and novel drug targets for cancer treatment

2021 ◽  
Vol 9 ◽  
pp. 205031212110670
Author(s):  
Zemene Demelash Kifle ◽  
Meklit Tadele ◽  
Eyerusalem Alemu ◽  
Tadele Gedamu ◽  
Akeberegn Gorems Ayele
Keyword(s):  
Drug Resistance ◽  
Cancer Treatment ◽  
Drug Targets ◽  
Therapeutic Agents ◽  
Chemotherapeutic Agents ◽  
Cross Resistance ◽  
Drug Induced ◽  
Induced Apoptosis ◽  
Novel Drug ◽  
Novel Drug Targets

Despite recent advances in cancer diagnosis, prevention, detection, as well as management, the disease is expected to be the top cause of death globally. The chemotherapy approach for cancer has become more advanced in its design, yet no medication can cure enough against all types of cancer and its stage. Thus, this review aimed to summarize a recent development of new therapeutic agents and novel drug targets for the treatment of cancer. Several obstacles stand in the way of effective cancer treatment and drug development, including inaccessibility of tumor site by appropriate drug concentration, debilitating untoward effects caused by non-selective tissue distribution of chemotherapeutic agents, and occurrence of drug resistance, which leads to cross-resistance to a variety of drugs. Resistance to treatment with anticancer drugs results from multiple factors and the most common reason for acquiring drug resistance is marking and expelling drugs that prevent cancer cells to be targeted by chemotherapeutic agents. Moreover, insensitivity to drug-induced apoptosis, alteration, and mutation of drug target and interference/change of DNA replication are other main causes of treatment failure.

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