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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] ABSTRACT: Patient-derived cell transplantation is an attractive therapy for regenerative medicine. However, this requires effective strategies to reliably differentiate patient cells into clinically useful cell types. Herein, we report the discovery that 5-nitro-5′hydroxy-indirubin-3′oxime (5′-HNIO) is a novel inducer of cell transdifferentiation. 5′-HNIO induced muscle transdifferentiation into adipogenic and osteogenic cells. 5′-HNIO was shown to inhibit aurora kinase A, which is a known cell fate regulator. 5′-HNIO produced a favorable level of transdifferentiation compared to other aurora kinase inhibitors and induced transdifferentiation across cell lineage boundaries. Significantly, 5′-HNIO treatment produced direct transdifferentiation without up-regulating potentially oncogenic induced pluripotent stem cell (iPSC) reprogramming factors. Thus, our results demonstrate that 5′-HNIO is an attractive molecular tool for cell transdifferentiation and cell fate research.
Archiv der Pharmazie 11/2014; 347(11). DOI:10.1002/ardp.201400223 · 1.53 Impact Factor
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