Links between DNA polymerase beta expression and sensitivity to bleomycin

Liu, Shukun; Lai, Yanhao; Zhao, Wei; Wu, Mei; Zhang, Zunzhen

doi:10.1016/j.tox.2011.01.008

Cited by 12 publications

(14 citation statements)

References 27 publications

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“…3,4 While BER is critical for maintaining the genome integrity of healthy cells, it is a hindrance for anti-cancer modalities that target DNA. 5 Consequently, the enzymes involved in BER are inhibition targets. 6–12 There are an increasing number of examples of BER enzyme inhibitors that potentiate the effects of cytotoxic DNA damaging agents.…”

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confidence: 99%

Synergistic Effects of an Irreversible DNA Polymerase Inhibitor and DNA Damaging Agents on HeLa Cells

2017

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DNA repair is vital to maintaining genome integrity, but thwarts the effects of cytotoxic agents that target nucleic acids. Consequently, repair enzymes are potential targets for molecules that modulate cell function and anti-cancer therapeutics. DNA polymerase β (Pol β) is an attractive target because it plays a key role in base excision repair (BER), a primary pathway that repairs the effects of many DNA damaging agents. We previously identified an irreversible inhibitor of Pol β whose design was based upon a DNA lesion that inactivates Pol β and its back up BER enzyme, DNA polymerase λ (Pol λ). Using this molecule as a starting point we characterized an irreversible inhibitor (13) of Pol β (IC50 = 0.4 μM) and Pol λ (IC50 = 1.0 μM) from a 130-member library of candidates that is ~50-fold more effective against Pol β. Pro-13 (5 μM) is only slightly cytotoxic to human cervical cancer cells (HeLa), but potentiates the cytotoxicity of methyl methanesulfonate (MMS). DNA isolated from HeLa cells treated with MMS contain a ~3-fold greater amount of abasic sites when pro-13 is present, consistent with inhibition of DNA repair. Proinhibitor pro-13 continues to induce cytotoxicity in DNA damaged cells following MMS removal. HeLa cell cytotoxicity is increased ~100-fold following a 8 h incubation with pro-13 after cells that were originally subjected to conditions under which 20% of the cells survive and reproduce. The potentiation of MMS cytotoxicity by pro-13 is greater than any previously reported BER enzyme repair inhibitor.

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confidence: 99%

Synergistic Effects of an Irreversible DNA Polymerase Inhibitor and DNA Damaging Agents on HeLa Cells

2017

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“…For instance, POLβ-null MEFs exhibit a severe hypersensitivity to monofunctional DNA alkylating agents, such as MMS, methylnitrosourea, and ethyl methane sulfonate (EMS) [22], as well as a more mild hypersensitivity to the radiomimetic antibiotic bleomycin [135]. After treatment with MMS, an accumulation of single-stranded DNA breaks is observed in POLβ-null MEFs [136], reflective of incomplete BER.…”

Section: Ber Proteins In Clinical Treatmentsmentioning

confidence: 99%

Base Excision Repair: Contribution to Tumorigenesis and Target in Anticancer Treatment Paradigms

Illuzzi¹,

Wilson²

2012

CMC

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Cancer treatments often lose their effectiveness due to the development of multiple drug resistance. Thus, identification of key proteins involved in the tumorigenic process and the survival mechanism(s), coupled with the design of novel therapeutic compounds (such as small molecule inhibitors), are essential steps towards the establishment of improved anticancer treatment strategies. DNA repair pathways and their proteins have been exposed as potential targets for combinatorial anticancer therapies that involve DNA-interactive cytotoxins, such as alkylating agents, because of their central role in providing resistance against DNA damage. In addition, an understanding of the tumor-specific genetics and associated DNA repair capacity has allowed research scientists and clinicians to begin to devise more targeted treatment strategies based on the concept of synthetic lethality. In this review, the repair mechanisms, as well as the links to cancer progression and treatment, of three key proteins that function in the base excision repair pathway, i.e. APE1, POLβ, and FEN1, are discussed.

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“…27–29 Links between DNA pol β expression and sensitivity to BLM also support the ability of pol β to attenuate BLM toxicity. 30 BLM also caused double-strand breaks that may be the primary source of toxicity. Double-strand breaks are repaired by homologous recombination (HR), nonhomologous end joining (NHEJ), and alternative NHEJ.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, inhibition of pol β sensitizes the cells to bleomycin damage, 27–29 while increased expression of pol β attenuates BLM toxicity. 30 …”

Section: Introductionmentioning

confidence: 99%

Honokiol Inhibits DNA Polymerases β and λ and Increases Bleomycin Sensitivity of Human Cancer Cells

Gowda

Suo

Spratt

2017

Chem. Res. Toxicol.

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A major concept to sensitize cancer cells to DNA damaging agents is by inhibiting proteins in the DNA repair pathways. X-family DNA polymerases play critical roles in both base excision repair (BER) and nonhomologous end joining (NHEJ). In this study, we examined the effectiveness of honokiol to inhibit human DNA polymerase β (pol β), which is involved in BER, and DNA polymerase λ (pol λ), which is involved in NHEJ. Kinetic analysis with purified polymerases showed that honokiol inhibited DNA polymerase activity. The inhibition mode for the polymerases was a mixed-function noncompetitive inhibition with respect to the substrate, dCTP. The X-family polymerases, pol β and pol λ, were slightly more sensitive to inhibition by honokiol based on the Ki value of 4.0 μM for pol β, and 8.3 μM for pol λ, while the Ki values for pol η and Kf were 20 and 26 μM, respectively. Next we extended our studies to determine the effect of honokiol on the cytotoxicity of bleomycin and temozolomide in human cancer cell lines A549, MCF7, PANC-1, UACC903, and normal blood lymphocytes (GM12878). Bleomycin causes both single strand DNA damage that is repaired by BER and double strand breaks that are repaired by NHEJ, while temozolomide causes methylation damage repaired by BER and O6-alkylguanine-DNA alkyltransferase. The greatest effects were found with the honokiol and bleomycin combination in MCF7, PANC-1, and UACC903 cells, in which the EC50 values were decreased 10-fold. The temozolomide and honokiol combination was less effective; the EC50 values decreased three-fold due to the combination. It is hypothesized that the greater effect of honokiol on bleomycin is due to inhibition of the repair of the single strand and double strand damage. The synergistic activity shown by the combination of bleomycin and honokiol suggests that they can be used as combination therapy for treatment of cancer, which will decrease the therapeutic dosage and side effects of bleomycin.

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Links between DNA polymerase beta expression and sensitivity to bleomycin

Cited by 12 publications

References 27 publications

Synergistic Effects of an Irreversible DNA Polymerase Inhibitor and DNA Damaging Agents on HeLa Cells

Synergistic Effects of an Irreversible DNA Polymerase Inhibitor and DNA Damaging Agents on HeLa Cells

Base Excision Repair: Contribution to Tumorigenesis and Target in Anticancer Treatment Paradigms

Honokiol Inhibits DNA Polymerases β and λ and Increases Bleomycin Sensitivity of Human Cancer Cells

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