Potentiation of tumour apoptosis by human growth hormone via glutathione production and decreased NF-κB activity

Cherbonnier, Claire; Déas, Olivier; Carvalho, Gabrielle; Vassal, Gilles; Dürrbach, Antoine; Haeffner, Astrid; Charpentier, B; Bénard, Jean; Hirsch, François

doi:10.1038/sj.bjc.6601223

Cited by 13 publications

(6 citation statements)

References 66 publications

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“…101 Human growth hormone (GH) can sensitize the AML cell line U937 to TNF or anthracyclin-induced apoptosis via inhibition of NF-kB. 105 Similarly, erythropoietin 106 can sensitize U937 cells to daunorubicin-induced apoptosis. This effect involves an EPO-induced activation of JAK2 and stabilization of IkB.…”

Section: Therapeutic Strategies Targeting Nf-jbmentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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The transcription factor nuclear factor kappa B (NF-jB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-jB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-jB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-jB-activatory kinase IjB kinase, of the proteaseome, or of the DNA binding of NF-jB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-jB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-jB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

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Section: Therapeutic Strategies Targeting Nf-jbmentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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“…EMSAs NF-kB measurement by EMSAs was performed as reported (Cherbonnier et al, 2003). Renal carcinoma cell lines were cultured for 2 h in the absence or in the presence of 2 mM of VBL alone or in addition to various doses of EPO.…”

Section: Luciferase Reporter Assaysmentioning

confidence: 99%

“…Recently, it has been described that human growth hormone (GH) can sensitize U937 cells to TNF or daunorubicin (Dauno)-induced apoptosis by inhibiting the NF-kB pathway (Cherbonnier et al, 2002;Cherbonnier et al, 2003). Since the receptors for GH and erythropoietin (EPO) share structural features (Bazan, 1990) and both similarly activate the JAK2/ STAT5 pathway (Parganas et al, 1998), we wondered whether EPO might be used as an NF-kB-inhibitory, chemosensitizing agent.…”

Section: Introductionmentioning

confidence: 99%

Chemosensitization by erythropoietin through inhibition of the NF-κB rescue pathway

Carvalho

Lefaucheur²,

Cherbonnier³

et al. 2004

Oncogene

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Two cell lines that exemplify erythropoietin (EPO) receptor-positive tumors, human renal carcinoma cell lines RCC and the myelomonocytic leukemia cell line U937, were investigated for the apoptosis-modulatory potential of EPO. Cells cultured in the presence of EPO exhibited an elevated apoptotic response to cancer chemotherapeutic agents such as daunorubicin (Dauno) and vinblastine (VBL). Chemosensitization by EPO did not involve an increase in p53 activation, yet correlated with enhanced Bax/Bak-dependent mitochondrial membrane perturbation and caspase maturation. In vitro monotherapy with Dauno or VBL induced the degradation of IjBa, provoked the translocation of NF-jB p65/50 to the nucleus and stimulated the expression of an NF-jBactivatable reporter gene. All these signs of NF-jB activation were perturbed in the presence of EPO. Inhibition of JAK2, one of the receptor-proximal elements of EPO-mediated signal transduction, greatly diminished the EPO-mediated chemosensitization and NF-jB inhibition. EPO lost its death-facilitating effects in the presence of an NF-jB inhibitor, underscoring the cause-effect relationship between EPO-mediated chemosensitization and NF-jB inhibition. Altogether, these results suggest that, at least in a specific subset of tumors, EPO receptor agonists can prevent activation of the NF-jB pathway, thereby enhancing the propensity of EPO receptorpositive tumor cells to undergo apoptosis. Oncogene (2005) 24, 737-745.

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“…Released NFnB migrates into the nucleus and activates target gene expression (28,29). It has been shown that inhibition of NFnB activation can result in increased sensitivity to anthracyclines (30,31 (34). Our study revealed that the expression of IKBKE was significantly associated with daunorubicin cytotoxicity.…”

Section: Discussionmentioning

confidence: 51%

Genetic Variants Contributing to Daunorubicin-Induced Cytotoxicity

Huang

Duan

Kistner³

et al. 2008

Cancer Research

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Identifying heritable genetic variants responsible for chemotherapeutic toxicities has been challenging due in part to its multigenic nature. To date, there is a paucity of data on genetic variants associated with patients experiencing severe myelosuppression or cardiac toxicity following treatment with daunorubicin. We present a genome-wide model using International HapMap cell lines that integrate genotype and gene expression to identify genetic variants that contribute to daunorubicin-induced cytotoxicity. A cell growth inhibition assay was used to measure variations in the cytotoxicity of daunorubicin. Gene expression was determined using the Affymetrix GeneChip Human Exon 1.0ST Array. Using sequential analysis, we evaluated the associations between genotype and cytotoxicity, those significant genotypes with gene expression and correlated gene expression of the identified candidates with cytotoxicity. A total of 26, 9, and 18 genetic variants were identified to contribute to daunorubicininduced cytotoxicity through their effect on 16, 9, and 36 gene expressions in the combined, Centre d' Etude du Polymorphisme Humain (CEPH), and Yoruban populations, respectively. Using 50 non-HapMap CEPH cell lines, single nucleotide polymorphisms generated through our model predicted 29% of the overall variation in daunorubicin sensitivity and the expression of CYP1B1 was significantly correlated with sensitivity to daunorubicin. In the CEPH validation set, rs120525235 and rs3750518 were significant predictors of transformed daunorubicin IC 50 (P = 0.005 and P = 0.0008, respectively), and rs1551315 trends toward significance (P = 0.089). This unbiased method can be used to elucidate genetic variants contributing to a wide range of cellular phenotypes. [Cancer Res 2008;68(9):3161-8]

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Potentiation of tumour apoptosis by human growth hormone via glutathione production and decreased NF-κB activity

Cited by 13 publications

References 66 publications

Targeting NF-κB in hematologic malignancies

Targeting NF-κB in hematologic malignancies

Chemosensitization by erythropoietin through inhibition of the NF-κB rescue pathway

Genetic Variants Contributing to Daunorubicin-Induced Cytotoxicity

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