Benznidazole modulates cell proliferation in acute leukemia cells

Calvo, Karina Lucrecia; Ronco, Marı́a Teresa; Noguera, Nélida I.; García, Fernando

doi:10.3109/08923973.2013.811597

Cited by 8 publications

(12 citation statements)

References 45 publications

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“…Western blot was used to evaluate the expression level of NRF2 and Keap1 [36]. Cell pellets were re-suspended in lysis buffer containing 10 mM Tris-HCl (pH 7.4), 5 mM etilendiammonotetracetico (EDTA) (Sigma-Aldrich, St. Louis, MO, USA)., 150 mM NaCl, 1% Triton X-100, 250 µM orthovanadate, 20 mM β-glycerophosphate and protease inhibitors (Sigma-Aldrich).…”

Section: Western Blot Analysismentioning

confidence: 99%

PML/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells

Banella

Catalano

Travaglini

et al. 2019

Cancers

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NRF2 (NF-E2 p45-related factor 2) orchestrates cellular adaptive responses to stress. Its quantity and subcellular location is controlled through a complex network and its activity increases during redox perturbation, inflammation, growth factor stimulation, and energy fluxes. Even before all-trans retinoic acid (ATRA) treatment era it was a common experience that acute promyelocytic leukemia (APL) cells are highly sensitive to first line chemotherapy. Since we demonstrated how high doses of ascorbate (ASC) preferentially kill leukemic blast cells from APL patients, we aimed to define the underlying mechanism and found that promyelocytic leukemia/retinoic acid receptor α (PML/RARa) inhibits NRF2 function, impedes its transfer to the nucleus and enhances its degradation in the cytoplasm. Such loss of NRF2 function alters cell metabolism, demarcating APL tissue from both normal promyelocytes and other acute myeloide leukemia (AML) blast cells. Resistance to ATRA/arsenic trioxide (ATO) treatment is rare but grave and the metabolically-oriented treatment with high doses of ASC, which is highly effective on APL cells and harmless on normal hematopoietic stem cells (HSCs), could be of use in preventing clonal evolution and in rescuing APL-resistant patients.

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Section: Western Blot Analysismentioning

confidence: 99%

PML/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells

Banella

Catalano

Travaglini

et al. 2019

Cancers

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“…For the clonogenicity assay, the drug-treated cells were washed in PBS, plated in 6-well plates at 3,000 and 300 cells/well, respectively, and further incubated under the conventional (normoxic) tissue culture condition. 31 As shown in Fig. 2, both the SK-N-ER and MDA-MB-231 tumor cells treated by Benznidazole under the hypoxic condition completely lost their clonogenic potential even at the high seeding density of 3 cells/mm 2 .…”

Section: Benznidazole Specifically Inhibits Clonogenic Growth Of Tumomentioning

confidence: 79%

“…We have found that Benznidazole does not appear to activate apoptosis based on PARP1 cleavage, which is also consistent with the literature. 31 Nevertheless, we could not rule out the possibilities that Benznidazole could trigger other forms or pathways of cell death, including mitotic catastrophe and/or necrosis, either directly by itself or via its reduced metabolites. As a hallmark of their cell-killing effects, hypoxia-activated cytotoxins cause DNA doublestranded breaks likely via free radicals generated by the oneelectron reduction, which can lead to cell death.…”

Section: Discussionmentioning

confidence: 97%

“…These results are also consistent with a previous report showing that Benznidazole, when used at up to 1 mM, does not induce significant apoptosis of acute leukemia cells. 31 The chemically active metabolic products of hypoxia-activated cytotoxic agents can potentially react with a wide range of cellular macromolecules. As a hallmark of their cytotoxicity, hypoxia-activated cytotoxins induce DNA damages and double-stranded breaks.…”

Section: Dose-and Po 2 -Dependent Clonogenic Inhibition By Benznidazolementioning

confidence: 99%

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Hypoxia-activated cytotoxicity of benznidazole against clonogenic tumor cells

Lin

Yun

2016

Cancer Biology & Therapy

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Solid tumors contain numerous regions with insufficient oxygen concentrations, a condition termed hypoxia. Tumor hypoxia is significantly associated with metastasis, refractory to conventional cancer therapies, and poor patient survival. Therefore, eradication of hypoxic tumor cells will likely have significant impact on the overall progression-free patient survival. This article reports a new discovery that Benznidazole, a bioreductive drug currently used to treat Chagas disease caused by the parasitic protozoan Trypanosoma cruzi, is activated by hypoxia and can kill clonogenic tumor cells especially those under severe hypoxic conditions (0.1 % O 2 ). This type of hypoxia selectivity is important in that severely hypoxic tumor microenvironment is where tumor cells exhibit the strongest resistance to therapy. Mechanistically, activation of Benznidazole coincides with the stabilization of the Hypoxia-Inducible Factor 1a (HIF-1a), suggesting that Benznidazole is activated after tumor cells have entered into a fully hypoxic state. Under such hypoxic conditions, Benznidazole induces the formation of 53BP1 foci, a hallmark of DNA doublestranded breaks that can cause clonogenic inhibition or cell death. These results demonstrate that Benznidazole is a hypoxia-activated cytotoxin with the potential to specifically eliminate hypoxic tumor cells.

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“…2), are known for their biological activity on Trypanosoma cruzi, [5] an agent of Chagas disease, and can also be of value in cancer research [6]. 4-Nitroimidazoles such as azathioprine (IMUREL ® ) ( Fig.…”

mentioning

confidence: 99%