Characterization of the effects of cisplatin and carboplatin on cell cycle progression and DNA damage response activation in DNA polymerase eta-deficient human cells

Cruet-Hennequart, Séverine; Villalan, Sangamitra; Kaczmarczyk, Agnieszka; O’Meara, Elaine; Sokòl, Anna M.; Carty, Michael P.

doi:10.4161/cc.8.18.9624

Cited by 46 publications

(55 citation statements)

References 73 publications

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“…It is well known that platinum-based drugs, such as CDDP, cause DNA damage (28)(29)(30)34). Both cisplatin and carboplatin induce DNA damage, primarily at guanine residues, generating monoadducts and interstrand crosslinks leading to inhibition of DNA replication, transcription, and ultimately to cell death (28)(29)(30)34).…”

Section: Discussionmentioning

confidence: 99%

“…Both cisplatin and carboplatin induce DNA damage, primarily at guanine residues, generating monoadducts and interstrand crosslinks leading to inhibition of DNA replication, transcription, and ultimately to cell death (28)(29)(30)34). In our study, we examined the effect of Notch pathway inhibition by GSI on DNA damage by observing the phosphorylation of histone γ-H2AX foci.…”

Section: Discussionmentioning

confidence: 99%

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Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy

McAuliffe¹,

Morgan²,

Wyant³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

296

252

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Chemoresistance to platinum therapy is a major obstacle that needs to be overcome in the treatment of ovarian cancer patients. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). This study demonstrates that the Notch signaling pathway and Notch3 in particular are critical for the regulation of CSCs and tumor resistance to platinum. We show that Notch3 overexpression in tumor cells results in expansion of CSCs and increased platinum chemoresistance. In contrast, γ-secretase inhibitor (GSI), a Notch pathway inhibitor, depletes CSCs and increases tumor sensitivity to platinum. Similarly, a Notch3 siRNA knockdown increases the response to platinum therapy, further demonstrating that modulation of tumor chemosensitivity by GSI is Notch specific. Most importantly, the cisplatin/GSI combination is the only treatment that effectively eliminates both CSCs and the bulk of tumor cells, indicating that a dual combination targeting both populations is needed for tumor eradication. In addition, we found that the cisplatin/GSI combination therapy has a synergistic cytotoxic effect in Notch-dependent tumor cells by enhancing the DNA-damage response, G 2 /M cell-cycle arrest, and apoptosis. Based on these results, we conclude that targeting the Notch pathway could significantly increase tumor sensitivity to platinum therapy. Our study suggests important clinical applications for targeting Notch as part of novel treatment strategies upon diagnosis of ovarian cancer and at recurrence. Both platinum-resistant and platinum-sensitive relapses may benefit from such an approach as clinical data suggest that all relapses after platinum therapy are increasingly platinum resistant.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy

McAuliffe¹,

Morgan²,

Wyant³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

296

252

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“…Following treatment with doxorubicin, cell cycle progression was analyzed by flow cytometry [16] using a FACSCalibur or a FACSCanto II instrument. Data was analyzed using CellQuest™ software, and Diva™ software.…”

Section: Flow Cytometrymentioning

confidence: 99%

Doxorubicin induces the DNA damage response in cultured human mesenchymal stem cells

et al. 2012

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Anthracyclines including doxorubicin are widely used in the treatment of leukemia. While the effects of doxorubicin on hematopoietic cells have been characterized, less is known about the response of human mesenchymal stem cells (hMSCs) in the bone marrow stroma to anthracyclines. We characterized the effect of doxorubicin on key DNA damage responses in hMSCs, and compared doxorubicin sensitivity and DNA damage response activation between isolated hMSCs and the chronic myelogenous leukemia (CML) cell line, K562.Phosphorylation of H2AX, Chk1 and RPA2 was more strongly activated in K562 cells than in hMSCs, at equivalent doses of doxorubicin. hMSCs were relatively resistant to doxorubicin such that following exposure to 15μM doxorubicin, the level of cleaved caspase-3 detected by western blotting was lower in hMSCs compared to K562 cells. Flow cytometric analysis of cell cycle progression demonstrated that exposure to doxorubicin induced G2/M phase arrest in hMSCs, while, 48 hours after exposure, 17% of cells were apoptotic as determined from the percentage of cells having sub-G1 DNA content. We also show that the doxorubicin sensitivity of hMSCs isolated from a healthy donor was comparable to that of hMSCs isolated from a chronic lymphocytic leukemia (CLL) patient. Overall, our results demonstrate that high doses of doxorubicin induce the DNA damage response in hMSCs, and that cultured hMSCs are relatively resistant to doxorubicin.

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“…However, not all cytotoxic agents targeting DNA or inducing S phase arrest provoke [ 18 F]FLT flare. For example, cisplatin induces DNA damage by crosslinking, which does not increase FLT uptake (2,9,10). To date, no individualized evaluation of cytotoxic agents for [ 18 F]FLT flare has been undertaken.…”

Section: Introductionmentioning

confidence: 99%

Etoposide increases equilibrative nucleoside transporter 1 activity and fluorothymidine uptake: Screening of 60 cytotoxic agents

Lee

2012

Oncology Reports

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H]FLT uptake accompanying cell cycle arrest at S/G2/M phase and the increase in TK1 expression and activity in both ENT1-low expressing HT29 and ENT1-high expressing MDA-MB-231 cells. The inhibition of ENT1 activity by dipyridamol or S-(p-nitrobenzyl)-6-thioinosine repressed the etoposide-induced cell death in HeLa cells, whereas it induced no changes in the other cell lines. In conclusion, etoposide is identified as a potent inducer for ENT1 activity and [ 3 H]FLT uptake. The role of ENT1 activity by etoposide was cell-type dependent, which requests caution for the application of ENT1-mediated [ 18 F]FLT flare for treatment monitoring.

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Characterization of the effects of cisplatin and carboplatin on cell cycle progression and DNA damage response activation in DNA polymerase eta-deficient human cells

Cited by 46 publications

References 73 publications

Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy

Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy

Doxorubicin induces the DNA damage response in cultured human mesenchymal stem cells

Etoposide increases equilibrative nucleoside transporter 1 activity and fluorothymidine uptake: Screening of 60 cytotoxic agents

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