Small PARP inhibitor PJ-34 induces cell cycle arrest and apoptosis of adult T-cell leukemia cells

Bai, Xue; Moles, Ramona; Chaib-Mezrag, Hassiba; Nicot, Christophe

doi:10.1186/s13045-015-0217-2

Cited by 28 publications

(18 citation statements)

References 45 publications

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“…Furthermore, there was only a slight increase in the SubG1 cell subpopulation across all cell lines treated with rucaparib compared to DMSO control, suggesting that cells are not undergoing apoptosis. These results are in line with those of Jelinic and Levine who observed low SubG1 events in cancer cells treated with olaparib or veliparib [ 49 ].…”

Section: Discussionsupporting

confidence: 92%

“…These results demonstrate that the synergistic effect on growth inhibition observed for the combination of rucaparib and Nutlin-3/RG7388 is not the result of an accentuated p53 response and hence not related to the p53 molecular pathway. The interplay between PARP and p53 is controversial which may be related to the type of DNA damage, type of PARP inhibitors and intensity of replicative stress [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

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Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer

et al. 2017

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Ovarian cancer is the seventh most common cancer worldwide for females and the most lethal of all gynecological malignancies. The treatment of ovarian cancer remains a challenge in spite of advances in debulking surgery and changes in both chemotherapy schedules and routes of administration. Cancer treatment has recently been improving with the introduction of targeted therapies to achieve greater specificity and less cytotoxicity. Both PARP inhibitors and MDM2-p53 binding antagonists are targeted therapeutic agents entered into clinical trials. This preclinical study evaluated the effect of Nutlin-3/RG7388 and rucaparib as single agents and in combination together in a panel of ovarian cancer cell lines. Median-drug-effect analysis showed Nutlin-3/RG7388 combination with rucaparib was additive to, or synergistic in a cell type-dependent manner. Mechanism studies showed rucaparib alone had no effect on p53 stabilization or activity. Although treatment with Nutlin-3 or RG7388 induced stabilization of p53 and upregulation of p21WAF1 and MDM2, the addition of rucaparib did not enhance the p53 activation seen with the MDM2 inhibitors alone. These results demonstrate that the synergistic effect on growth inhibition observed in the combination between rucaparib and Nutlin-3/RG7388 is not the result of increased p53 molecular pathway activation. Nevertheless, combined treatment of Nutlin-3/RG7388 with rucaparib increased cell cycle arrest and apoptosis, which was marked for A2780 and IGROV-1. These data indicate that combination treatment with MDM2 inhibitors and rucaparib has synergistic and dose reduction potential for the treatment of ovarian cancer, dependent on cell type.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer

et al. 2017

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“…Their effectiveness for these cancers is primarily due to their ability to affect the repair of DNA strand breaks . There is also evidence of PARPi having effectiveness in other haematologic malignancies such as leukaemia . PARPi have not been specifically tested for benefit in MF.…”

Section: Resultsmentioning

confidence: 99%

Therapeutic and prognostic significance of PARP‐1 in advanced mycosis fungoides and Sezary syndrome

Lemchak

Banerjee

Digambar

et al. 2017

Experimental Dermatology

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While mycosis fungoides (MF) is typically an indolent malignancy, it may infrequently undertake an aggressive course. We used proteomic analyses to identify a biomarker of the aggressive course of MF. Results of this investigation demonstrated that PARP-1, heat-shock protein family A (Hsp70) member 1 like (HSAP1L), Hsp70 member 1A (HSPA1A), ATP-depending RNA helicase (DDX17) and the α-isoform of lamina-associated polypeptide 2 (TMPO) had higher expression in aggressive disease versus non-aggressive. Moreover, PARP-1 was overexpressed in patients with early stage of MF who developed later an aggressive disease. PARP-1 was evaluated as a new target for therapy, demonstrating the selective dose-dependent cytotoxic effect of PARP inhibitors on Sézary cells in comparison with non-malignant lymphocytes. In conclusion, we believe that PARP-1 may serve not only as a biomarker at initial biopsies for a disease that may become aggressive but also as a new therapeutic target of advanced MF and Sézary syndrome.

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“…The projected 4-year survival rates of patients with the acute and lymphoma forms are only 1–5% [56]. DNA repair inhibitors induced cell death in different human leukemias [57, 58], and in the absence of an effective treatment for ATLL, we decided to test the cytotoxicity of a WRN helicase inhibitor. WRN helicases are involved in HR DNA repair and helicase activity is required during DNA replication.…”

Section: Discussionmentioning

confidence: 99%

WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells

et al. 2016

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BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) infection is associated with adult T-cell leukemia/lymphoma (ATLL), a lymphoproliferative malignancy with a dismal prognosis and limited therapeutic options. Recent evidence shows that HTLV-1-transformed cells present defects in both DNA replication and DNA repair, suggesting that these cells might be particularly sensitive to treatment with a small helicase inhibitor. Because the “Werner syndrome ATP-dependent helicase” encoded by the WRN gene plays important roles in both cellular proliferation and DNA repair, we hypothesized that inhibition of WRN activity could be used as a new strategy to target ATLL cells.MethodsOur analysis demonstrates an apoptotic effect induced by the WRN helicase inhibitor in HTLV-1-transformed cells in vitro and ATL-derived cell lines. Inhibition of cellular proliferation and induction of apoptosis were demonstrated with cell cycle analysis, XTT proliferation assay, clonogenic assay, annexin V staining, and measurement of mitochondrial transmembrane potential.ResultsTargeted inhibition of the WRN helicase induced cell cycle arrest and apoptosis in HTLV-1-transformed leukemia cells. Treatment with NSC 19630 (WRN inhibitor) induces S-phase cell cycle arrest, disruption of the mitochondrial membrane potential, and decreased expression of anti-apoptotic factor Bcl-2. These events were associated with activation of caspase-3-dependent apoptosis in ATL cells. We identified some ATL cells, ATL-55T and LMY1, less sensitive to NSC 19630 but sensitive to another WRN inhibitor, NSC 617145.ConclusionsWRN is essential for survival of ATL cells. Our studies suggest that targeting the WRN helicase with small inhibitors is a novel promising strategy to target HTLV-1-transformed ATL cells.

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Small PARP inhibitor PJ-34 induces cell cycle arrest and apoptosis of adult T-cell leukemia cells

Cited by 28 publications

References 45 publications

Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer

Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer

Therapeutic and prognostic significance of PARP‐1 in advanced mycosis fungoides and Sezary syndrome

WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells

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