DNA-Damaging Agents in Cancer Chemotherapy: Serendipity and Chemical Biology

Cheung-Ong, Kahlin; Giaever, Guri; Nislow, Corey

doi:10.1016/j.chembiol.2013.04.007

Cited by 502 publications

(406 citation statements)

References 92 publications

Supporting

Mentioning

377

Contrasting

Unclassified

Order By: Relevance

“…Many alkylating agents such as cyclophosphamide and temozolomide induce DNA damage by attaching an alkyl group to adenine or guanine, leading to replication fork stalling and subsequent apoptosis [17] . These DNA lesions are mainly repaired by base excision repair (BER).…”

Section: Repair Of Base Alkylation and Ssbmentioning

confidence: 99%

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Wang

2015

WJBC

View full text Add to dashboard Cite

The identification of cancer stem cells (CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells, CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response (DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored.

show abstract

Section: Repair Of Base Alkylation and Ssbmentioning

confidence: 99%

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Wang

2015

WJBC

View full text Add to dashboard Cite

show abstract

“…Depending upon the functionality of each of the DNA repair pathways in a tumor, certain types of DNA damage are less well tolerated than others. Many types of DNA-damaging therapeutics have been developed that utilize widely differing mechanisms of action (3). These differences in mechanism make it possible to find a therapy that is effective against cancers that are resistant to other types of DNA-damaging agents.…”

Section: Introductionmentioning

confidence: 99%

“…On the basis of these criteria, there are four main groups of DNA-damaging chemotherapeutics: alkylating agents, antimetabolites, topoisomerase inhibitors, and antitumor antibiotics. Most chemotherapeutics also have nonspecific cytotoxic effects that can contribute to patient toxicity (3).…”

Section: Introductionmentioning

confidence: 99%

LY2606368 Causes Replication Catastrophe and Antitumor Effects through CHK1-Dependent Mechanisms

King

Diaz

McNeely

et al. 2015

Molecular Cancer Therapeutics

153

175

View full text Add to dashboard Cite

CHK1 is a multifunctional protein kinase integral to both the cellular response to DNA damage and control of the number of active replication forks. CHK1 inhibitors are currently under investigation as chemopotentiating agents due to CHK1's role in establishing DNA damage checkpoints in the cell cycle. Here, we describe the characterization of a novel CHK1 inhibitor, LY2606368, which as a single agent causes double-stranded DNA breakage while simultaneously removing the protection of the DNA damage checkpoints. The action of LY2606368 is dependent upon inhibition of CHK1 and the corresponding increase in CDC25A activation of CDK2, which increases the number of replication forks while reducing their stability. Treatment of cells with LY2606368 results in the rapid appearance of TUNEL and pH2AX-positive double-stranded DNA breaks in the S-phase cell population. Loss of the CHK1-dependent DNA damage checkpoints permits cells with damaged DNA to proceed into early mitosis and die. The majority of treated mitotic nuclei consist of extensively fragmented chromosomes. Inhibition of apoptosis by the caspase inhibitor Z-VAD-FMK had no effect on chromosome fragmentation, indicating that LY2606368 causes replication catastrophe. Changes in the ratio of RPA2 to phosphorylated H2AX following LY2606368 treatment further support replication catastrophe as the mechanism of DNA damage. LY2606368 shows similar activity in xenograft tumor models, which results in significant tumor growth inhibition. LY2606368 is a potent representative of a novel class of drugs for the treatment of cancer that acts through replication catastrophe.

show abstract

“…The mainstay chemotherapeutics such as anthracyclines, cisplatin and radiomimetic drugs are often used to eliminate cancer cells and reduce the burden of tumors by inflicting damages to the genome [1][2][3]. These genotoxic agents are administered to cancer patients in combination, and in some cases with small molecule inhibitors to block DNA repair pathways with the aim of sensitizing cancer cells towards the chemotherapeutic regimens [4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%