5 '-OH-5-nitro-Indirubin oxime (AGM130), an Indirubin derivative, induces apoptosis of Imatinib-resistant chronic myeloid leukemia cells
School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea Leukemia research
(Impact Factor: 2.35).
01/2013; 37(4). DOI: 10.1016/j.leukres.2012.12.017
Imatinib is a highly effective drug for the treatment of chronic myeloid leukemia (CML) that targets the BCR-ABL kinase. However, a number of patients have CML that is resistant to Imatinib treatment. In this report, we developed AGM130 as a potential therapeutic drug for Imatinib-resistant CML treatment. The AGM130 compound is derived from Indirubin, which is an ingredient of Danggui Longhui Wan and known as a cyclin-dependent kinase (CDK) inhibitor. The water solubility of AGM130 is more enhanced than that of the original form of Indirubin, which has very poor water solubility. Our data showed that the AGM130 compound efficiently decreased the viability of CML-derived K562 cells. Moreover, this compound also efficiently decreased the viability of Imatinib-resistant K562 cells in in vitro and in vivo systems. In addition, like Indirubin, AGM130 also inhibited phosphorylation of retinoblastoma protein (Rb), which is a major substrate of CDK. Conclusively, our data suggest that AGM130 is a strong candidate for treating Imatinib-resistant CML.
Available from: Melis Arslanhan
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ABSTRACT: Chronic myeloid leukemia and systemic mastocytosis are myeloid neoplasms sharing a number of pathogenetic and clinical features. In both conditions, an aberrantly activated oncoprotein with tyrosine kinase activity, namely BCR-ABL1 in chronic myeloid leukemia, and mutant KIT, mostly KIT D816V, in systemic mastocytosis, is key to disease evolution. The appreciation of the role of such tyrosine kinases in these diseases has led to the development of improved therapies with tyrosine kinase-targeted inhibitors. However, most drugs, including new KIT D816V-blocking agents, have failed to achieve long-lasting remissions in advanced systemic mastocytosis, and there is a similar problem in chronic myeloid leukemia, where imatinib-resistant patients sometimes fail to achieve remission, even with second- or third-line BCR-ABL1 specific tyrosine kinase inhibitors. During disease progression, additional signaling pathways become activated in neoplastic cells, but most converge into major downstream networks. Among these, the AKT and STAT5 pathways appear most critical and may result in drug-resistant chronic myeloid leukemia and systemic mastocytosis. Inhibition of phosphorylation of these targets has proven their crucial role in disease-evolution in both malignancies. Together, these observations suggest that STAT5 and AKT are key drivers of oncogenesis in drug-resistant forms of the diseases, and that targeting STAT5 and AKT might be an interesting approach in these malignancies. The present article provides an overview of our current knowledge about the critical role of AKT and STAT5 in the pathophysiology of chronic myeloid leukemia and systemic mastocytosis and on their potential value as therapeutic targets in these neoplasms.
Haematologica 03/2014; 99(3):417-29. DOI:10.3324/haematol.2013.098442 · 5.81 Impact Factor
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ABSTRACT: Indirubin is an active ingredient mainly used to treat leukemia in China and is reported to be a leading inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) by competing with ATP binding sites. New findings have indicated that its comprehensive structure may contribute to its polypharmacological activities particularly in cancer and neurodegenerative disease therapy, as both of these diseases are usually accompanied by a common molecular link related to abnormal phosphorylation of CDKs and GSK-3. In the elderly, cancer and neurodegenerative disease are tightly associated common diseases and sometimes unavoidably co-exist. In this review, the underlying mechanisms of the dual actions of indirubin and its structurally-related compounds in cancer and neurodegenerative disease therapy are presented.
Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) 08/2014; 14(9). DOI:10.2174/1871520614666140825112924 · 2.47 Impact Factor
Available from: degruyter.com
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ABSTRACT: This study was conducted to clarify the effect of ultra-pressure treatment on the extraction of bioactive compounds from indigo plant leaves (Polygonum tinctorium Lour.) and on their properties. Leaves were harvested the in mid-August, 2013, from Naju City (Korea), and treated using two methods: ultra-pressure (550 MPa, 3 min) and hot-air (70°C, 24 h). Then, the leaves were ultrasonically extracted with methanol. The content of indirubin in leaves treated with ultra pressure and hot air was (535.55 ± 26.14) mg kg−1 and (52.63 ± 6.45) mg kg−1, respectively, and that of tryptanthrin was (165.55 ± 8.74) mg kg−1 and (153.00 ± 7.62) mg kg−1, respectively. Polyphenolic content in the leaves extract was (127.24 ± 13.67) mg kg−1 after the ultrapressure and (88.22 ± 5.33) mg kg−1 after the hot-air treatment. The content of flavonoids was (2298.67 ± 83.27) mg kg−1 after the ultra-pressure and (3224.00 ± 21.45) mg kg−1 after the hotair treatment. Di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium (DPPH) radical scavenging activities of the indigo extract obtained by ultra-pressure and hot-air treatment methods at the concentration of 1 mg mL−1 were (80.25 ± 0.73) % and (66.54 ± 2.35) %, respectively, and 2,2′-azinobis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical scavenging activities were estimated as (90.14 ± 0.79) % and (64.45 ± 8.97) %, respectively. The methanol leaf extract after ultra-pressure treatment exhibited higher binding properties to human serum albumin in comparison with catechin and conventional treatments. Consequently, it was assumed that the ultra-pressure treatment is an effective method for the extraction of bioactive compounds from indigo leaves.
Chemical Papers- Slovak Academy of Sciences 10/2014; 68(10). DOI:10.2478/s11696-014-0572-4 · 1.47 Impact Factor
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