Downregulation of c-Myc determines sensitivity to 2-methoxyestradiol–induced apoptosis in human acute myeloid leukemia

Chow, Julie Chi; Liu, Chien-Ru; Lin, Che-Pin; Lee, Chun-Nin; Cheng, Yun-Chih; Lin, Shufan; Liu, H. Eugene

doi:10.1016/j.exphem.2007.10.004

Cited by 18 publications

(18 citation statements)

References 38 publications

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“…MYC plays a role in cell cycle progression, apoptosis, and cellular transformation and is frequently amplified and overexpressed in prostate cancer (50). MYC is also known to protect cells against oxidative stress (51) and in leukemia cells, the oxidative stressinduced MYC mRNA downregulation has been identified as a mechanism of 2-methoxyestradiol-induced apoptosis (52). Thus, these results also support the idea that monensin induces growth inhibition by sensitizing prostate cancer cells to oxidative stress.…”

Section: Discussionsupporting

confidence: 76%

Monensin Is a Potent Inducer of Oxidative Stress and Inhibitor of Androgen Signaling Leading to Apoptosis in Prostate Cancer Cells

Ketola

Vainio²,

Fey³

et al. 2010

Molecular Cancer Therapeutics

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Current treatment options for advanced and hormone refractory prostate cancer are limited and responses to commonly used androgen pathway inhibitors are often unsatisfactory. Our recent results indicated that sodium ionophore monensin is one of the most potent and cancer-specific inhibitors in a systematic sensitivity testing of most known drugs and drug-like molecules in a panel of prostate cancer cell models. Because monensin has been extensively used in veterinary applications to build muscle mass in cattle, the link to prostate cancer and androgen signaling was particularly interesting. Here, we showed that monensin effects at nanomolar concentrations are linked to induction of apoptosis and potent reduction of androgen receptor mRNA and protein in prostate cancer cells. Monensin also elevated intracellular oxidative stress in prostate cancer cells as evidenced by increased generation of intracellular reactive oxygen species and by induction of a transcriptional profile characteristic of an oxidative stress response. Importantly, the antiproliferative effects of monensin were potentiated by combinatorial treatment with the antiandrogens and antagonized by antioxidant vitamin C. Taken together, our results suggest monensin as a potential well-tolerated, in vivo compatible drug with strong proapoptotic effects in prostate cancer cells, and synergistic effects with antiandrogens. Moreover, our data suggest a general strategy by which the effects of antiandrogens could be enhanced by combinatorial administration with agents that increase oxidative stress in prostate cancer cells. Mol Cancer Ther; 9(12); 3175-85. Ó2010 AACR.

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Section: Discussionsupporting

confidence: 76%

Monensin Is a Potent Inducer of Oxidative Stress and Inhibitor of Androgen Signaling Leading to Apoptosis in Prostate Cancer Cells

Ketola

Vainio²,

Fey³

et al. 2010

Molecular Cancer Therapeutics

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“…We have, therefore, screened for a compound that targets Hif-1α and shown that adaphostin, bortezomib, lenalidomide, and enzastaurin decrease Hif-1α levels and VEGF, dependent on c-Myc. Drug-induced decreases in c-Myc and/or Hif-1α levels have also been previously observed in response to 2ME2, 17-AAG, and pazopanib, which are antiangiogenic and effective in MM and/or other solid and hematologic malignancies (11,33,(45)(46)(47)(48)(49). (vehicle alone or 10 mg/kg adaphostin once weekly) was started when tumors were measurable.…”

Section: Discussionmentioning

confidence: 99%

Targeting Angiogenesis via a c-Myc/Hypoxia-Inducible Factor-1α–Dependent Pathway in Multiple Myeloma

Zhang

Sattler²,

Tonon

et al. 2009

Cancer Research

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Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1α (Hif-1α) expression in MM cells, which is associated with oncogenic c-Myc. A drug screen for anti-MM agents that decrease Hif-1α and c-Myc levels identified a variety of compounds, including bortezomib, lenalidomide, enzastaurin, and adaphostin. Functionally, based on transient knockdowns and overexpression, our data delineate a c-Myc/Hif-1α-dependent pathway mediating vascular endothelial growth factor production and secretion. The antiangiogenic activity of our tool compound, adaphostin, was subsequently shown in a zebrafish model and translated into a preclinical in vitro and in vivo model of MM in the bone marrow milieu. Our data, therefore, identify Hif-1α as a novel molecular target in MM and add another facet to anti-MM drug activity. [Cancer Res 2009;69(12):5082-90]

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“…However, the role of autophagy was not evaluated in these reports and apoptosis was designated as the main executioner of cell death. 154,155 Notably, although a clear cytoprotective function of autophagy after 2ME-stimulation has not been reported so far, the mechanisms of autophagy-mediated cell death are still unclear. An early induction of autophagy by 2ME (20 M) in Ewing sarcoma cells is required to stimulate apoptosis, and Atg7 or Beclin 1 siRNA knockdown results in the attenuation of apoptosis.…”

Section: Sod Catalase and Gsh Reductase Mimeticmentioning

confidence: 99%

“…82 Gao et al (2005) attributed the activation of JNK1 after 2ME treatment to the ROS-mediated (specifically H 2 O 2 and superoxide) suppression of Akt activation and Akt expression levels, followed by the inhibition of mTOR signaling. 154 In a later study, Akt repression by 2ME was linked to the inhibition of NFB, 155 two signaling pathways with an established role in the negative regulation of autophagy. However, the role of autophagy was not evaluated in these reports and apoptosis was designated as the main executioner of cell death.…”

Section: Sod Catalase and Gsh Reductase Mimeticmentioning

confidence: 99%

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

Dewaele¹,

Maes²,

Agostinis³

2010

Autophagy

277

199

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Downregulation of c-Myc determines sensitivity to 2-methoxyestradiol–induced apoptosis in human acute myeloid leukemia

Cited by 18 publications

References 38 publications

Monensin Is a Potent Inducer of Oxidative Stress and Inhibitor of Androgen Signaling Leading to Apoptosis in Prostate Cancer Cells

Monensin Is a Potent Inducer of Oxidative Stress and Inhibitor of Androgen Signaling Leading to Apoptosis in Prostate Cancer Cells

Targeting Angiogenesis via a c-Myc/Hypoxia-Inducible Factor-1α–Dependent Pathway in Multiple Myeloma

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

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