Monitoring DNA Damage Induced by Chemotherapeutic Agents as a Predictor of Clinical Outcome

2018 ◽  
pp. 209-250
Author(s):  
Soterios A. Kyrtopoulos
Keyword(s):  
Dna Damage ◽  
Clinical Outcome ◽  
Chemotherapeutic Agents

scholarly journals Regulation of p73-mediated apoptosis by c-Jun N-terminal kinase

2007 ◽  
Vol 405 (3) ◽  
pp. 617-623 ◽  
Author(s):  
Emma V. Jones ◽  
Mark J. Dickman ◽  
Alan J. Whitmarsh
Keyword(s):  
Dna Damage ◽  
Stress Responses ◽  
Tumour Progression ◽  
Chemotherapeutic Agents ◽  
Signalling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
P53 Family ◽  
Jnk Pathway ◽  
Mitogen Activated Protein ◽  
Induced Apoptosis

The JNK (c-Jun N-terminal kinase)/mitogen-activated protein kinase signalling pathway is a major mediator of stress responses in cells, including the response to DNA damage. DNA damage also causes the stabilization and activation of p73, a member of the p53 family of transcription factors. p73, like p53, can mediate apoptosis by up-regulating the expression of pro-apoptotic genes, including Bax (Bcl2-associated X protein) and PUMA (p53 up-regulated modulator of apoptosis). Changes in p73 expression have been linked to tumour progression, particularly in neuroblastomas, whereas in tumours that feature inactivated p53 there is evidence that p73 may mediate the apoptotic response to chemotherapeutic agents. In the present study, we demonstrate a novel link between the JNK signalling pathway and p73. We use pharmacological and genetic approaches to show that JNK is required for p73-mediated apoptosis induced by the DNA damaging agent cisplatin. JNK forms a complex with p73 and phosphorylates it at several serine and threonine residues. The mutation of JNK phosphorylation sites in p73 abrogates cisplatin-induced stabilization of p73 protein, leading to a reduction in p73 transcriptional activity and reduced p73-mediated apoptosis. Our results demonstrate that the JNK pathway is an important regulator of DNA damage-induced apoptosis mediated by p73.

scholarly journals Ubiquitin and Ubiquitin-Like Proteins Are Essential Regulators of DNA Damage Bypass

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2848
Author(s):  
Nicole A. Wilkinson ◽  
Katherine S. Mnuskin ◽  
Nicholas W. Ashton ◽  
Roger Woodgate
Keyword(s):  
Dna Damage ◽  
Cancer Progression ◽  
Chemotherapeutic Agents ◽  
Tumor Formation ◽  
Human Cells ◽  
Double Strand Breaks ◽  
Template Switching ◽  
Post Translational Modifications ◽  
Strand Breaks ◽  
Exogenous Factors

Many endogenous and exogenous factors can induce genomic instability in human cells, in the form of DNA damage and mutations, that predispose them to cancer development. Normal cells rely on DNA damage bypass pathways such as translesion synthesis (TLS) and template switching (TS) to replicate past lesions that might otherwise result in prolonged replication stress and lethal double-strand breaks (DSBs). However, due to the lower fidelity of the specialized polymerases involved in TLS, the activation and suppression of these pathways must be tightly regulated by post-translational modifications such as ubiquitination in order to limit the risk of mutagenesis. Many cancer cells rely on the deregulation of DNA damage bypass to promote carcinogenesis and tumor formation, often giving them heightened resistance to DNA damage from chemotherapeutic agents. In this review, we discuss the key functions of ubiquitin and ubiquitin-like proteins in regulating DNA damage bypass in human cells, and highlight ways in which these processes are both deregulated in cancer progression and might be targeted in cancer therapy.

scholarly journals A ”Clickable” Probe for Active MGMT in Glioblastoma Demonstrates Two Discrete Populations of MGMT

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 453 ◽  
Author(s):  
Sudhir Raghavan ◽  
David S. Baskin ◽  
Martyn A. Sharpe
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Cells ◽  
Dna Adducts ◽  
Alkylating Agents ◽  
Chemotherapeutic Agents ◽  
Dna Alkylation ◽  
Methylated Dna ◽  
Methylguanine Methyltransferase ◽  
Discrete Populations

Various pathways can repair DNA alkylation by chemotherapeutic agents such as temozolomide (TMZ). The enzyme O6-methylguanine methyltransferase (MGMT) removes O6-methylated DNA adducts, leading to the failure of chemotherapy in resistant glioblastomas. Because of the anti-chemotherapeutic activities of MGMT previously described, estimating the levels of active MGMT in cancer cells can be a significant predictor of response to alkylating agents. Current methods to detect MGMT in cells are indirect, complicated, time-intensive, or utilize molecules that require complex and multistep chemistry synthesis. Our design simulates DNA repair by the transfer of a clickable propargyl group from O6-propargyl guanine to active MGMT and subsequent attachment of fluorescein-linked PEG linker via ”click chemistry.” Visualization of active MGMT levels reveals discrete active and inactive MGMT populations with biphasic kinetics for MGMT inactivation in response to TMZ-induced DNA damage.

scholarly journals Inhibition of AKT-Signaling Sensitizes Soft Tissue Sarcomas (STS) and Gastrointestinal Stromal Tumors (GIST) to Doxorubicin via Targeting of Homology-Mediated DNA Repair

2020 ◽  
Vol 21 (22) ◽  
pp. 8842
Author(s):  
Sergei Boichuk ◽  
Firuza Bikinieva ◽  
Ilmira Nurgatina ◽  
Pavel Dunaev ◽  
Elena Valeeva ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Soft Tissue ◽  
Gastrointestinal Stromal Tumors ◽  
Topoisomerase Ii ◽  
Soft Tissue Sarcomas ◽  
Akt Signaling ◽  
Chemotherapeutic Agents ◽  
Tail Moment ◽  
Stromal Tumors

Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is well documented for a broad spectrum of human malignancies supporting their growth and progression. Accumulating evidence has also implicated AKT as a potent modulator of anti-cancer therapies via regulation of DNA damage response and repair (DDR) induced by certain chemotherapeutic agents and ionizing radiation (IR). In the present study, we examined the role of AKT signaling in regulating of Rad51 turnover and cytotoxic effects of topoisomerase II inhibitor, doxorubicin (Dox) in soft tissue sarcomas (STS) and gastrointestinal stromal tumors (GIST) in vitro. Blocking of AKT signaling (MK-2206) enhanced cytotoxic and pro-apoptotic effects of Dox in vast majority of STS and GIST cell lines. The phosphorylated form of Akt co-immunoprecipitates with Rad51 after Dox-induced DNA damage, whereas Akt inhibition interrupts this interaction and decreases Rad51 protein level by enhancing protein instability via proteasome-dependent degradation. Inhibition of Akt signaling in Dox-treated cells was associated with the increased number of γ-H2AX-positive cells, decrease of Rad51 foci formation and its colocalization with γ-H2AX foci, thereby revealing unsuccessful DDR events. This was also in consistency with an increase of tail moment (TM) and olive tail moment (OTM) in Dox-treated GIST and STS cells cultured in presence of Akt inhibitor after Dox washout. Altogether, our data illustrates that inhibition of AKT signaling is STS and GIST might potentiate the cytotoxic effect of topoisomerase II inhibitors via attenuating the homology-mediated DNA repair.

scholarly journals Maximal killing of lymphoma cells by DNA damage–inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim

Blood ◽  
2010 ◽  
Vol 116 (24) ◽  
pp. 5256-5267 ◽  
Author(s):  
Lina Happo ◽  
Mark S. Cragg ◽  
Belinda Phipson ◽  
Jon M. Haga ◽  
Elisa S. Jansen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Drug Resistance ◽  
Target Genes ◽  
B Cell Lymphoma ◽  
Chemotherapeutic Agents ◽  
Lymphoid Cells ◽  
Lymphoma Cells ◽  
P53 Target Genes

Abstract DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In Eμ-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in Eμ-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of Eμ-Myc/Puma−/−Noxa−/− lymphomas both in vitro and in vivo. Remarkably, c-MYC–driven lymphoma cell lines from Noxa−/−Puma−/−Bim−/− mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.

scholarly journals Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1501 ◽  
Author(s):  
Agnieszka Bojko ◽  
Joanna Czarnecka-Herok ◽  
Agata Charzynska ◽  
Michal Dabrowski ◽  
Ewa Sikora
Keyword(s):  
Dna Damage ◽  
Comparative Analysis ◽  
Cancer Cells ◽  
Chemotherapeutic Agents ◽  
Double Stranded Dna ◽  
Secretory Phenotype ◽  
Paclitaxel Treatment ◽  
Senescence Phenotype ◽  
Mcf 7 ◽  
Intermediate Effect

It is acknowledged that cancer cells are able to undergo senescence in response to clinically used chemotherapeutics. Moreover, recent years have provided evidence that some drugs can selectively remove senescent cells. Therefore, it is essential to properly identify and characterize senescent cells, especially when it comes to cancer. Senescence was induced in various cancer cell lines (A549, SH-SY-5Y, HCT116, MDA-MB-231, and MCF-7) following treatment with doxorubicin, irinotecan, methotrexate, 5-fluorouracil, oxaliplatin, or paclitaxel. Treatment with tested chemotherapeutics resulted in upregulation of p21 and proliferation arrest without cytotoxicity. A comparative analysis with the use of common senescence markers (i.e., morphology, SA-β-galactosidase, granularity, secretory phenotype, and the level of double-stranded DNA damage) revealed a large diversity in response to the chemotherapeutics used. The strongest senescence inducers were doxorubicin, irinotecan, and methotrexate; paclitaxel had an intermediate effect and oxaliplatin and 5-fluorouracil did not induce senescence. In addition, different susceptibility of cancer cells to senescence was observed. A statistical analysis aimed at finding any relationship between the senescence markers applied did not show clear correlations. Moreover, increased SA-β-gal activity coupled with p21 expression proved not to be an unequivocal senescence marker. This points to a need to simultaneously analyze multiple markers, given their individual limitations.

scholarly journals MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents

Oncogene ◽  
2016 ◽  
Vol 35 (45) ◽  
pp. 5905-5915 ◽  
Author(s):  
M Y Shah ◽  
E Martinez-Garcia ◽  
J M Phillip ◽  
A B Chambliss ◽  
R Popovic ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Chemotherapeutic Agents ◽  
Damage Repair

Novel first-in-class small molecule targeting APE1/Ref-1 to prevent and treat chemotherapy-induced peripheral neuropathy (CIPN).

2018 ◽  
Vol 36 (34_suppl) ◽  
pp. 229-229
Author(s):  
Mark R. Kelley ◽  
Richard Adam Messmann ◽  
Jill Fehrenbacher
Keyword(s):  
Dna Damage ◽  
Peripheral Neuropathy ◽  
Sensory Neurons ◽  
Small Molecule ◽  
Oxidative Dna Damage ◽  
Ex Vivo ◽  
Phase 1 ◽  
Chemotherapeutic Agents ◽  
Cellular Mechanisms ◽  
Effective Prevention

229 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is an acute and chronic debilitating side effect of a number of chemotherapeutic agents lacking FDA-approved interventions or strategies resulting in dose-limiting neurotoxicity. CIPN can persist following discontinuation of the drug with up to 40% of patients having continued CIPN five years after treatment ends. Thus, CIPN directly affects cancer survivorship, quality of life, and may limit future treatment options if cancer recurs. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage caused by anticancer therapies could contribute to the neuropathy. Methods: Using an experimental model of isolated sensory neurons in culture, we established a causal relationship between cancer-therapy-induced neurotoxicity and DNA damage and repair. Results: Genetically reducing the activity of APE1 increased the neurotoxicity produced by platin treatment, whereas augmenting the activity of APE1 lessened neurotoxicity. Furthermore, using a targeted small-molecule, APX3330, which increases DNA repair of APE1 in neurons, it lessened neurotoxicity using a variety of endpoints ex vivo; e.g. DNA damage, CGRP release. We will present data using animal models of CIPN demonstrating a protective effect of APX3330 using either cis- or oxaliplatin without diminishing the anti-tumor effect of the platins. A Phase 1 clinical trial for safety/RF2D for APX3330 has completed (NCT03375086). Conclusions: Effective prevention and management of CIPN hinges on understanding its pathophysiology. While multiple causal mechanisms may be at work, we believe that the induction of oxidative DNA damage in sensory neurons is a major cause of CIPN. Thus, enhancement of oxidative DNA damage repair by APX3330 results in reduction of CIPN.

scholarly journals DNA Damage during the Spindle-Assembly Checkpoint Degrades CDC25A, Inhibits Cyclin–CDC2 Complexes, and Reverses Cells to Interphase

2003 ◽  
Vol 14 (10) ◽  
pp. 3989-4002 ◽  
Author(s):  
Jeremy P.H. Chow ◽  
Wai Yi Siu ◽  
Tsz Kan Fung ◽  
Wan Mui Chan ◽  
Anita Lau ◽  
...  
Keyword(s):  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Histone H3 ◽  
Ectopic Expression ◽  
Spindle Assembly ◽  
Cyclin B1 ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Mitotic Block

Cell cycle checkpoints that monitor DNA damage and spindle assembly are essential for the maintenance of genetic integrity, and drugs that target these checkpoints are important chemotherapeutic agents. We have examined how cells respond to DNA damage while the spindle-assembly checkpoint is activated. Single cell electrophoresis and phosphorylation of histone H2AX indicated that several chemotherapeutic agents could induce DNA damage during mitotic block. DNA damage during mitotic block triggered CDC2 inactivation, histone H3 dephosphorylation, and chromosome decondensation. Cells did not progress into G1 but seemed to retract to a G2-like state containing 4N DNA content, with stabilized cyclin A and cyclin B1 binding to Thr14/Tyr15-phosphorylated CDC2. The loss of mitotic cells was not due to cell death because there was no discernible effect on caspase-3 activation, DNA fragmentation, or viability. Extensive DNA damage during mitotic block inactivated cyclin B1-CDC2 and prevented G1 entry when the block was removed. The mitotic DNA damage responses were independent of p53 and pRb, but they were dependent on ATM. CDC25A that accumulated during mitosis was rapidly destroyed after DNA damage in an ATM-dependent manner. Ectopic expression of CDC25A or nonphosphorylatable CDC2 effectively inhibited the dephosphorylation of histone H3 after DNA damage. Hence, although spindle disruption and DNA damage provide conflicting signals to regulate CDC2, the negative regulation by the DNA damage checkpoint could overcome the positive regulation by the spindle-assembly checkpoint.

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