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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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Figure 4. Chemical structures of natural product-based DNA damaging therapeutics.
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Figure 4: Figure 4. Chemical structures of natural product-based DNA damaging therapeutics.

Mentions: Blockage of DNA replication is often an effective therapy for rapidly dividing cells and can be achieved either through direct DNA damage or indirectly through inhibition of replication proteins such as that observed with topoisomerase inhibitors, camptothecin and etoposide (Fig. 4A). Numerous anti-metabolites target DNA metabolism for instance thymidylate synthase, ribonucleotide reductase and dihydrofolate reductase, via agents including 5-fluorouracil, gemcitabine and methotrexate respectively and are often used in combination (Fig. 3F and G).76 These agents along with the laboratory workhorse for inducing replication stress, HU, are strong activators of the ATR pathway. Similar to HU, gemcitabine has been demonstrated to inhibit ribonucleotide reductase; thus, the activation of ATR is not unexpected.77 However, gemcitabine can also be incorporated into a growing DNA chain acting as a chain terminator like cytosine arabinoside (Ara-C). Interestingly Ara-C sensitivity is increased in cells with defective ATR signaling77 suggesting that in the ATR activation via gemcitabine is, in part, a function of both its activities, inhibition of ribonucleotide reductase and acting as a chain terminator. This data are consistent with a more recent finding that the small molecule ATR VE82 sensitizes cells to gemcitibine71 treatment suggesting that ATR inhibition could be an effective strategy to increase the anti-cancer activity of gem and other DNA damaging therapeutics that activates the ATR pathway.


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

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

Figure 4. Chemical structures of natural product-based DNA damaging therapeutics.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Figure 4. Chemical structures of natural product-based DNA damaging therapeutics.
Mentions: Blockage of DNA replication is often an effective therapy for rapidly dividing cells and can be achieved either through direct DNA damage or indirectly through inhibition of replication proteins such as that observed with topoisomerase inhibitors, camptothecin and etoposide (Fig. 4A). Numerous anti-metabolites target DNA metabolism for instance thymidylate synthase, ribonucleotide reductase and dihydrofolate reductase, via agents including 5-fluorouracil, gemcitabine and methotrexate respectively and are often used in combination (Fig. 3F and G).76 These agents along with the laboratory workhorse for inducing replication stress, HU, are strong activators of the ATR pathway. Similar to HU, gemcitabine has been demonstrated to inhibit ribonucleotide reductase; thus, the activation of ATR is not unexpected.77 However, gemcitabine can also be incorporated into a growing DNA chain acting as a chain terminator like cytosine arabinoside (Ara-C). Interestingly Ara-C sensitivity is increased in cells with defective ATR signaling77 suggesting that in the ATR activation via gemcitabine is, in part, a function of both its activities, inhibition of ribonucleotide reductase and acting as a chain terminator. This data are consistent with a more recent finding that the small molecule ATR VE82 sensitizes cells to gemcitibine71 treatment suggesting that ATR inhibition could be an effective strategy to increase the anti-cancer activity of gem and other DNA damaging therapeutics that activates the ATR pathway.

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