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Chemotherapy induced DNA damage response: convergence of drugs and pathways.

Woods D, Turchi JJ - Cancer Biol. Ther. (2013)

Bottom Line: Chemotherapeutics target rapidly dividing cancer cells by directly or indirectly inducing DNA damage.However, the activation of these various pathways has similar results including DNA repair, suppression of global general translation, cell cycle arrest and, ultimately, either cell survival or cell death.This review will focus on a series of chemotherapy-induced DNA lesions and highlight recent advances in our understanding of the DDR, the DNA repair pathways it activates and the cellular consequences of these converging pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.

ABSTRACT
Chemotherapeutics target rapidly dividing cancer cells by directly or indirectly inducing DNA damage. Upon recognizing DNA damage, cells initiate a variety of signaling pathways collectively referred to as the DNA damage response (DDR). Interestingly, the pathways used to elicit this response are as varied as the types of DNA damage induced. However, the activation of these various pathways has similar results including DNA repair, suppression of global general translation, cell cycle arrest and, ultimately, either cell survival or cell death. This review will focus on a series of chemotherapy-induced DNA lesions and highlight recent advances in our understanding of the DDR, the DNA repair pathways it activates and the cellular consequences of these converging pathways.

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Related in: MedlinePlus

Figure 3. Chemical structures of DNA damaging chemotherapeutics.
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Figure 3: Figure 3. Chemical structures of DNA damaging chemotherapeutics.

Mentions: Alkylating agents are perhaps the oldest class of agents used to treat cancer and result in the covalent transfer of alkyl-groups to DNA resulting in DNA damage and includes nitrogen mustards and nitrosoureas (Fig. 3A and B). There has been considerable recent excitement over bendamustine, an alkylating agent originally developed in the 1960s and approved in 2008 for treatment of lymphoma.57 Despite the recent clinical implementation, there is dearth information concerning its mechanism of action.58 While bendamustine forms mono adducts on purine bases as a function of the 2-cloroethylamine moiety, there is only limited evidence for the formation of purine intra or interstrand crosslinks.59 Significant levels of DNA double strand breaks have been observed when compared with comparable alkylating agents.60 COMPARE analysis revealed limited similarity with other agents including similar alkylating agents like melphalan.58 Gene ontology analyses of Bendamustine treated cells indicated DDR as the top regulated pathway with some evidence that the BER pathway is in part responsible for processing bendamustine induced DNA adducts.58 While there is also evidence that melphalan mono and di-adducts melphalan are repaired via the NER pathway as demonstrated by the hypersensitivity of NER deficient cells to treatment,61 this has not been addressed for bendamustine. Bendamustine activation of the DDR has been studied in a few models. Initial studies in a myeloma cancer model revealed activation of ATM and Chk2, but not Chk1.62 However this study was limited by use of non-specific DDR inhibitors which led to the conclusion that inhibition of ATM/ATR Chk1/2 does not alter bendamustine sensitivity. More recently in a nice series of experiments, a more specific inhibitor of Chk1 (AZD7762) was shown to potentiate the activity of both melphalan and bendamustine which did so with an accompanying increase Chk2 phosphorylation.63 The authors suggested that this sensitivity was a function of the generation of more DNA DSBs, though this was not directly measured. A study of the effects of differing doses of Bendamustine revealed differential activation of cell cycle checkpoints, consistent with the multiple mechanisms of bendamustine action.64 The same study also revealed increased sensitivity to the Chk1 inhibitor UCN-01 but not a Chk2 inhibitor consistent with an ATR Chk1 driven DDR pathway. Clearly it will be of interest to determine if ATR inhibitors alter sensitivity to Bendamustine and melphalan treatment.


Chemotherapy induced DNA damage response: convergence of drugs and pathways.

Woods D, Turchi JJ - Cancer Biol. Ther. (2013)

Figure 3. Chemical structures of DNA damaging chemotherapeutics.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672181&req=5

Figure 3: Figure 3. Chemical structures of DNA damaging chemotherapeutics.
Mentions: Alkylating agents are perhaps the oldest class of agents used to treat cancer and result in the covalent transfer of alkyl-groups to DNA resulting in DNA damage and includes nitrogen mustards and nitrosoureas (Fig. 3A and B). There has been considerable recent excitement over bendamustine, an alkylating agent originally developed in the 1960s and approved in 2008 for treatment of lymphoma.57 Despite the recent clinical implementation, there is dearth information concerning its mechanism of action.58 While bendamustine forms mono adducts on purine bases as a function of the 2-cloroethylamine moiety, there is only limited evidence for the formation of purine intra or interstrand crosslinks.59 Significant levels of DNA double strand breaks have been observed when compared with comparable alkylating agents.60 COMPARE analysis revealed limited similarity with other agents including similar alkylating agents like melphalan.58 Gene ontology analyses of Bendamustine treated cells indicated DDR as the top regulated pathway with some evidence that the BER pathway is in part responsible for processing bendamustine induced DNA adducts.58 While there is also evidence that melphalan mono and di-adducts melphalan are repaired via the NER pathway as demonstrated by the hypersensitivity of NER deficient cells to treatment,61 this has not been addressed for bendamustine. Bendamustine activation of the DDR has been studied in a few models. Initial studies in a myeloma cancer model revealed activation of ATM and Chk2, but not Chk1.62 However this study was limited by use of non-specific DDR inhibitors which led to the conclusion that inhibition of ATM/ATR Chk1/2 does not alter bendamustine sensitivity. More recently in a nice series of experiments, a more specific inhibitor of Chk1 (AZD7762) was shown to potentiate the activity of both melphalan and bendamustine which did so with an accompanying increase Chk2 phosphorylation.63 The authors suggested that this sensitivity was a function of the generation of more DNA DSBs, though this was not directly measured. A study of the effects of differing doses of Bendamustine revealed differential activation of cell cycle checkpoints, consistent with the multiple mechanisms of bendamustine action.64 The same study also revealed increased sensitivity to the Chk1 inhibitor UCN-01 but not a Chk2 inhibitor consistent with an ATR Chk1 driven DDR pathway. Clearly it will be of interest to determine if ATR inhibitors alter sensitivity to Bendamustine and melphalan treatment.

Bottom Line: Chemotherapeutics target rapidly dividing cancer cells by directly or indirectly inducing DNA damage.However, the activation of these various pathways has similar results including DNA repair, suppression of global general translation, cell cycle arrest and, ultimately, either cell survival or cell death.This review will focus on a series of chemotherapy-induced DNA lesions and highlight recent advances in our understanding of the DDR, the DNA repair pathways it activates and the cellular consequences of these converging pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.

ABSTRACT
Chemotherapeutics target rapidly dividing cancer cells by directly or indirectly inducing DNA damage. Upon recognizing DNA damage, cells initiate a variety of signaling pathways collectively referred to as the DNA damage response (DDR). Interestingly, the pathways used to elicit this response are as varied as the types of DNA damage induced. However, the activation of these various pathways has similar results including DNA repair, suppression of global general translation, cell cycle arrest and, ultimately, either cell survival or cell death. This review will focus on a series of chemotherapy-induced DNA lesions and highlight recent advances in our understanding of the DDR, the DNA repair pathways it activates and the cellular consequences of these converging pathways.

Show MeSH
Related in: MedlinePlus