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

Carvalho, Gabrielle; Lefaucheur, Carmen; Cherbonnier, Claire; Métivier, Didier; Chapel, Alain; Pallardy, Marc; Bourgeade, Marie‐Françoise; Charpentier, B; Hirsch, François; Kroemer, Guido

doi:10.1038/sj.onc.1208205

Cited by 49 publications

(38 citation statements)

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“…EPO also induced resistance to cisplatin in human malignant glioma cells and in a primary cervical cancer cell line (11). In contrast to these observations, one study showed that EPO failed to interfere with the antitumor effects of cisplatin against xenografts of lung cancer (12), whereas another report suggests that EPO chemosensitized human renal carcinoma and myleomonocytic leukemia cells to danuorubicin and vinblastine (13). With regard to radiation, studies have shown contradictory results, with EPO conferring resistance in glioma and cervical cancer cells (11), acting as a radiosensitizer through reduction of hypoxia in glioblastoma cells (14,15) or failing to alter radiation sensitivity in HeLa cells (5).…”

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confidence: 71%

Erythropoietin Fails to Interfere with the Antiproliferative and Cytotoxic Effects of Antitumor Drugs

Gewirtz

Walker

et al. 2006

Clinical Cancer Research

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Purpose: Erythropoietin (EPO) therapy is widely used for the prevention and treatment of anemia resulting from cancer chemotherapy. Native EPO regulates erythropoiesis, at least in part, by protecting erythroid progenitor cells from apoptotic cell death. The recent discovery of the EPO receptor (EPOR) on cancer cells raises the concern that EPO therapy might stimulate tumor growth and/or protect cancer cells from drug-induced apoptosis. Therefore, the capacity of EPO to interfere with the effects of conventional chemotherapeutic drugs on proliferation, apoptosis, and the induction of senescence was investigated in MCF-7 and MDA-MB231breast tumor cells, which express the EPOR as well as in F-MEL erythroleukemia cells. Experimental Design: Breast cancer cells and F-MEL leukemic cells were cultured in the presence or absence of EPO and then exposed to antitumor drugs. Cell proliferation was assessed by a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction assay 72 hours after drug exposure. Cytotoxicity was monitored by clonogenic survival. Apoptosis was evaluated either by the terminal deoxyribonucleotide transferase^mediated nick-end labeling assay or fluorescence-activated cell sorting analysis, and senescence was monitored by hgalactosidase staining. EPO signaling was assessed by monitoring the phosphorylation/activation of specific signaling proteins. Results: EPO failed to stimulate the proliferation of MCF-7 or MDA-MB231 breast tumor cells or F-MEL leukemic cells. EPO treatment also failed to interfere with the antiproliferative and/or cytotoxic effects of Adriamycin, Taxol, and tamoxifen in breast tumor cells (or of cytarabine and daunorubicin in F-MEL cells). EPO failed to prevent apoptosis induced by Taxol or senescence induced by Adriamycin in MCF-7 cells. EPO stimulated the activation of extracellular signalregulated kinase, p38, and c-Jun-NH 2 -kinase in MCF-7 cells but did not activate Akt or signal transducers and activators of transcription 5 (STAT5). EPO failed to activate any of these signaling pathways in MDA-MB231cells. Cytarabine and daunorubicin interfered with EPO signaling in F-MEL cells. Conclusions:These findings suggest that EPO is unlikely to directly counteract the effectiveness of cancer chemotherapeutic drugs. This may be a consequence of either ineffective signaling through the EPOR or drug-mediated suppression of EPO signaling.Cancer chemotherapy is often accompanied by severe and debilitating anemia due to both inhibition of erythroid cell maturation in the bone marrow and interference with the ability of the kidney to produce erythropoietin (EPO), the hormone that regulates red blood cell development. Chemotherapy-associated anemia is treated either with EPO in its native form (epoetin-a or epoetin-h, Epogen or Procrit) or a genetically modified form of the drug (Darbepoetin, Aranesp) or transfusion.Because of the potential of EPO to stimulate proliferation of hematopoietic and/or leukemic cells (which may express receptors for EPO and resp...

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confidence: 71%

Erythropoietin Fails to Interfere with the Antiproliferative and Cytotoxic Effects of Antitumor Drugs

Gewirtz

Walker

et al. 2006

Clinical Cancer Research

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“…One group has reported that RCCs undergo a higher degree of apoptosis with a combination of daunorubicin or vinblastine and Epo than with either of these agents alone. 46 In contrast to this chemosensitization Epo was found to cause resistance to cis-platin in HeLa 19 and to dacarbazine in melanoma cells. 29 In the latter studies, extremely high Epo concentrations were necessary, which were about 1,000-fold higher than the plasma concentration reached in cancer patients under rhESA therapy.…”

Section: Discussionmentioning

confidence: 99%

Lack of functional erythropoietin receptors of cancer cell lines

Laugsch¹,

Metzen²,

Svensson³

et al. 2007

Intl Journal of Cancer

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Erythropoietin (Epo) therapy reduces red cell transfusion requirements and improves the quality of life of anemic cancer patients receiving chemotherapy. However, there is concern that Epo may promote tumor growth. We investigated by real‐time RT‐PCR, immunofluorescence microscopy, Western blotting and cell growth analysis whether human cancer cell lines (SH‐SY5Y, MCF7, HepG2, U2‐OS, HeLa, HEK293T, RCC4, HCT116, 7860wt and SW480) possess functional Epo receptors (EpoR). We detected EpoR mRNA in all cell lines. Neither hypoxia nor Epo treatment altered the level of EpoR mRNA expression. Four commonly used commercial antibodies proved to be unsuitable for immunoblot procedures because they cross‐reacted with several proteins unrelated with EpoR. Depending on the antibody used, EpoR was localized to the plasma membrane, the cytoplasm or the nucleus. Experiments with small interfering RNA showed that EpoR protein was not expressed by the tumor cells except by UT7/Epo leukemia cells, which served as an EpoR positive control line, and by cells transfected with the human EpoR gene. Apart from UT7/Epo, none of the tumor cell lines responded to Epo treatment with phosphorylation of signaling molecules or with cell proliferation. © 2007 Wiley‐Liss, Inc.

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“…Thalidomide-induced apoptosis in MM cells is associated with downregulation of NF-kB DNA-binding activity and down-modulation of NF-kB targets such as c-IAP2 and c-FLIP. 100 Malignant cells exhibiting constitutive NF-kB activation are relatively resistant to chemo-or radiotherapy, and NF-kB inhibitors increase their sensitivity to such anticancer treatments, 3,101 presumably by downmodulating antiapoptotic NF-kB target genes such as c-IAPs, c-FLIP, Bcl-2, and Bcl-X L . 5 In B-precursor acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, NF-kB is activated by treatment with anthracyclines, known to favor the nuclear translocation of NF-kB subunits, 102 or by irradiation.…”

Section: Therapeutic Strategies Targeting Nf-jbmentioning

confidence: 99%

“…104 Moreover, the activation of physiological signal transduction pathways that inhibit constitutive activation of NF-kB may represent a strategy to overcome anthracycline resistance. 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.…”

Section: Therapeutic Strategies Targeting Nf-jbmentioning

confidence: 99%

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

Cited by 49 publications

References 50 publications

Erythropoietin Fails to Interfere with the Antiproliferative and Cytotoxic Effects of Antitumor Drugs

Erythropoietin Fails to Interfere with the Antiproliferative and Cytotoxic Effects of Antitumor Drugs

Lack of functional erythropoietin receptors of cancer cell lines

Targeting NF-κB in hematologic malignancies

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