Small-Molecule Inhibitors of DNA Damage-Repair Pathways: An Approach to Overcome Tumor Resistance to Alkylating Anticancer Drugs

Srinivasan, Ajay; Gold, Barry

doi:10.4155/fmc.12.58

Cited by 25 publications

(20 citation statements)

References 133 publications

(119 reference statements)

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“…DNA damage created by alkylation agents would lead to apoptosis and is one of the major mechanisms of cytotoxic anticancer drugs such as TMZ (61,62). We have demonstrated that rhein inhibits ALKBH2 and ALKBH3 in vitro and synergistically suppresses the proliferation of U87 cells during exposure to MMS (Fig.…”

Section: Discussionmentioning

confidence: 89%

Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage

Huang

Liu

et al. 2016

Journal of Biological Chemistry

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The AlkB repair enzymes, including Escherichia coli AlkB and two human homologues, ALKBH2 and ALKBH3, are iron(II)-and 2-oxoglutarate-dependent dioxygenases that efficiently repair N 1 -methyladenine and N 3 -methylcytosine methylated DNA damages. The development of small molecule inhibitors of these enzymes has seen less success. Here we have characterized a previously discovered natural product rhein and tested its ability to inhibit AlkB repair enzymes in vitro and to sensitize cells to methyl methane sulfonate that mainly produces N 1 -methyladenine and N 3 -methylcytosine lesions. Our investigation of the mechanism of rhein inhibition reveals that rhein binds to AlkB repair enzymes in vitro and promotes thermal stability in vivo. In addition, we have determined a new structural complex of rhein bound to AlkB, which shows that rhein binds to a different part of the active site in AlkB than it binds to in fat mass and obesity-associated protein (FTO). With the support of these observations, we put forth the hypothesis that AlkB repair enzymes would be effective pharmacological targets for cancer treatment.The nucleic acids in living cells are subject to modification by both endogenous and environmental agents (1). Direct-acting chemicals constantly damage nucleic acids and generate various methyl lesions with mutagenic and/or cytotoxic consequences (2, 3). O 6 -Methylguanine (O 6 mG) 2 and N 3 -methyladenine lesions have the highest potential for methylating damage by an SN1 agent such as N-methyl-NЈ-nitro-N-nitrosoguanidine (MNNG), which block replication and are thought to be toxic (4, 5). For the most part, the SN2 agent such as methyl methane sulfonate (MMS) produces N 1 -methyladenine (m 1 A) and N 3 -methylcytosine (m 3 C) lesions in single-stranded DNA (ssDNA). Accumulation of these adducts can lead to cell death (6, 7). Organisms have evolved several mechanisms to efficiently remove various methyl lesions, including suicidal methyltransferases, DNA glycosylases, and the AlkB family dioxygenases (see Fig. 1A) (8, 9). To date, AlkB repair appears to be the major natural defense mechanism with the power to restore the canonical base structure in vivo. Escherichia coli AlkB and its human homologues, ALKBH2 and ALKBH3, utilize iron(II) and 2-oxoglutarate (2OG) to achieve oxidative demethylation of m 1 A and m 3 C (see Fig. 1B) (10 -12). The lack of AlkB repair results in increased sensitivity to MMS, elevated level of mutations, and reduced cell proliferation (13-16). Furthermore, the accumulation of m 1 A and m 3 C lesions could also occur on RNA. Research suggests that the oxidative demethylation in mRNA and tRNA acts as a part of AlkB or ALKBH3 repair to protect cells against MMS (17, 18). The scope of substrates for AlkB repair has been largely extended to all simple N-alkyl lesions at the WatsonCrick base-pairing interface on the four bases (19), thus indicating the importance of oxidative demethylation for cell survival. In addition, human enzymes have been broadly linked to cancer. The housekeeping ...

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Section: Discussionmentioning

confidence: 89%

Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage

Huang

Liu

et al. 2016

Journal of Biological Chemistry

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“…Finally, the ability of FM-HCR to identify agents that either inhibit or enhance DRC in human cells (Fig. 4 C and D) opens the door to screens for novel compounds that might be used either to potentiate the effects of DNA damage-based anticancer agents or to mitigate the deleterious effects of environmental exposure to DNA-damaging agents (57)(58)(59).…”

Section: Discussionmentioning

confidence: 99%

Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis

Nagel

Margulies

Chaim

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

131

161

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The capacity to repair different types of DNA damage varies among individuals, making them more or less susceptible to the detrimental health consequences of damage exposures. Current methods for measuring DNA repair capacity (DRC) are relatively labor intensive, often indirect, and usually limited to a single repair pathway. Here, we describe a fluorescence-based multiplex flow-cytometric host cell reactivation assay (FM-HCR) that measures the ability of human cells to repair plasmid reporters, each bearing a different type of DNA damage or different doses of the same type of DNA damage. FM-HCR simultaneously measures repair capacity in any four of the following pathways: nucleotide excision repair, mismatch repair, base excision repair, nonhomologous end joining, homologous recombination, and methylguanine methyltransferase. We show that FM-HCR can measure interindividual DRC differences in a panel of 24 cell lines derived from genetically diverse, apparently healthy individuals, and we show that FM-HCR may be used to identify inhibitors or enhancers of DRC. We further develop a next-generation sequencing-based HCR assay (HCR-Seq) that detects rare transcriptional mutagenesis events due to lesion bypass by RNA polymerase, providing an added dimension to DRC measurements. FM-HCR and HCR-Seq provide powerful tools for exploring relationships among global DRC, disease susceptibility, and optimal treatment.

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“…33 On the other hand, DNA repair ability of tumor cells prevents the accumulation of lethal DNA damage from cytotoxic agents and ionizing radiation, which leads to tumor resistance. 34,35 Therefore, DDR plays a central role in tumorigenesis and cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Tumor protein D52 represents a negative regulator of ATM protein levels

et al. 2013

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Small-Molecule Inhibitors of DNA Damage-Repair Pathways: An Approach to Overcome Tumor Resistance to Alkylating Anticancer Drugs

Cited by 25 publications

References 133 publications

Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage

Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage

Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis

Tumor protein D52 represents a negative regulator of ATM protein levels

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