Recombinant human arginase induced caspase-dependent apoptosis and autophagy in non-Hodgkin’s lymphoma cells

Zeng, Xian; Li, Yubin; Fan, Jiajun; Hu, Zhao; Xian, Zongshu; Sun, Yun; Z, Wang; Wang, S; Zhang, G; Ju, Dianwen

doi:10.1038/cddis.2013.359

Cited by 48 publications

(42 citation statements)

References 40 publications

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“…50 Tumor-specific arginine requirements and the concurrent use of drugs to drive cell death along a particular mechanistic pathway may explain tumor-specific effects of arginine depletion. [51][52][53] RNA sequencing of sensitive and resistant samples identified 20 genes which predict response to arginine depletion. Pathway analysis confirmed that expression of arginine recycling or transport molecules did not correlate with sensitivity to arginine depletion.…”

Section: Discussionmentioning

confidence: 99%

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Mussai

Egan

Higginbotham-Jones

et al. 2015

Blood

139

153

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Key Points• Arginase depletion with BCT-100 pegylated recombinant human arginase is cytotoxic to AML blasts.Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters CAT-1 and CAT-2B, and that the majority of newly diagnosed patients' blasts have deficiencies in the arginine-recycling pathway enzymes argininosuccinate synthase and ornithine transcarbamylase, making them arginine auxotrophic. BCT-100, a pegylated human recombinant arginase, leads to a rapid depletion in extracellular and intracellular arginine concentrations, resulting in arrest of AML blast proliferation and a reduction in AML engraftment in vivo. BCT-100 as a single agent causes significant death of AML blasts from adults and children, and acts synergistically in combination with cytarabine. Using RNA sequencing, 20 further candidate genes which correlated with resistance have been identified. Thus, AML blasts are dependent on arginine for survival and proliferation, as well as depletion of arginine with BCT-100 of clinical value in the treatment of AML. (Blood. 2015;125(15):2386-2396

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Section: Discussionmentioning

confidence: 99%

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Mussai

Egan

Higginbotham-Jones

et al. 2015

Blood

139

153

View full text Add to dashboard Cite

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“…Mitochondrial membrane potential was monitored after cells were staining with JC-1 mitochondrial membrane potential assay kit (Beyotime, C2006) as previously described. 60 For apoptosis and mitochondrial membrane potential analysis, 30,000 cells were analyzed per sample. Cells were stained with PtdIns (Beyotime, C1052) and cell cycle was analyzed using flow cytometry as previously described.…”

Section: Flow Cytometry Analysismentioning

confidence: 99%

Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia

Zeng

Zhao

et al. 2015

Autophagy

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The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL(+) CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL(+) CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL(+) cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL(+) cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance.

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“…One example is the use of arginase, which degrades arginine and induces apoptosis in cancer cells (30). A previous study indicated that cancer cells are resistant to arginine deprivation in a three-dimensional environment (31).…”

Section: Discussionmentioning

confidence: 99%

Proliferation and motility of hepatocellular, pancreatic and gastric cancer cells grown in a medium without glucose and arginine, but with galactose and ornithine

et al. 2017

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Abstract. Human primary hepatocytes are able to survive in a medium without glucose and arginine, but supplemented with galactose and ornithine (hepatocyte selection medium; HSM). To address the possibility of the application of HSM in cancer therapy, hepatocellular carcinoma cells, pancreatic cancer cells and gastric cancer cells were cultured in HSM. Cell proliferation was analyzed using an MTS assay. Morphological changes were analyzed using hematoxylin and eosin staining. Apoptosis was analyzed using a TUNEL assay and cell motility was assessed with a scratch assay. Cell proliferation was significantly suppressed in cell lines grown in HSM (P<0.01 in all the cell lines). Hematoxylin and eosin staining revealed pyknotic nuclei, suggesting that these cells had undergone apoptosis. The number of TUNEL-positive cells was significantly increased in HSM. In the scratch assay, the distance between the growing edge and the scratched edge was significantly lower (P<0.01 in all the cell lines) in cells cultured in HSM, compared with those grown in Dulbecco's modified Eagle's medium or RPMI-1640. Therefore, the proliferation and motility of hepatocellular carcinoma cells, pancreatic cancer cells and gastric cancer cells was suppressed, and these cells subsequently underwent apoptosis in a medium without glucose and arginine, but containing galactose and ornithine.

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Recombinant human arginase induced caspase-dependent apoptosis and autophagy in non-Hodgkin’s lymphoma cells

Cited by 48 publications

References 40 publications

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target

Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia

Proliferation and motility of hepatocellular, pancreatic and gastric cancer cells grown in a medium without glucose and arginine, but with galactose and ornithine

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