Resveratrol induces apoptosis of human chronic myelogenous leukemia cells in vitro through p38 and JNK-regulated H2AX phosphorylation.

Posted by rob on January 27, 2015 under Uncategorized | Comments are off for this article

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Resveratrol induces apoptosis of human chronic myelogenous leukemia cells in vitro through p38 and JNK-regulated H2AX phosphorylation.

Acta Pharmacol Sin. 2015 Jan 26;

Authors: Wu XP, Xiong M, Xu CS, Duan LN, Dong YQ, Luo Y, Niu TH, Lu CR

Abstract

Aim:The phosphorylation of histone H2AX, a novel tumor suppressor protein, is involved in regulation of cancer cell apoptosis. The aim of this study was to examine whether H2AX phosphorylation was required for resveratrol-induced apoptosis of human chronic myelogenous leukemia (CML) cells in vitro.Methods:K562 cells were tested. Cell apoptosis was analyzed using flow cytometry, and the phosphorylation of H2AX and other signaling proteins was examined with Western blotting. To analyze the signaling pathways, the cells were transfected with lentiviral vectors encoding H2AX-wt or specific siRNAs.Results:Treatment of K562 cells with resveratrol (20-100 ?mol/L) induced apoptosis and phosphorylation of H2AX at Ser139 in time- and dose-dependent manners, but reduced phosphorylation of histone H3 at Ser10. Resveratrol treatment activated two MAPK family members p38 and JNK, and blocked the activation of another MAPK family member ERK. Pretreatment with the p38 inhibitor SB202190 or the JNK inhibitor SP600125 dose-dependently reduced resveratrol-induced phosphorylation of H2AX, which were also observed when the cells were transfected with p38- or JNK-specific siRNAs. Overexpression of H2AX in K562 cells markedly increased resveratrol-induced apoptosis, whereas overexpression of H2AX-139m (Ser139 was mutated to block phosphorylation) inhibited resveratrol-induced apoptosis. K562 cells transfected with H2AX-specific siRNAs were resistant to resveratrol-induced apoptosis.Conclusion:H2AX phosphorylation at Ser139 in human CML cells, which is regulated by p38 and JNK, is essential for resveratrol-induced apoptosis.

PMID: 25619392 [PubMed - as supplied by publisher]

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Granulocytic Sarcoma of the Uterus: A Rare Presentation of Extramedullary Relapse of AML and Importance of MRI.

Posted by rob on January 24, 2015 under Uncategorized | Comments are off for this article

Granulocytic Sarcoma of the Uterus: A Rare Presentation of Extramedullary Relapse of AML and Importance of MRI.

Case Rep Radiol. 2014;2014:501342

Authors: Ucar M, Guryildirim M

Abstract

Granulocytic sarcoma (GS) is a solid tumor that is the extramedullary presentation of acute myelogenous leukemia, other myeloproliferative disorders, or myelodysplastic syndromes. Less commonly, it also may arise as an isolated mass. In this report, we describe a 23-year-old female patient, with a GS in the uterus and we stress the value of diffusion weighted imaging for the evaluation of uterine neoplasms. To our knowledge, our case is the first in the literature to report diffusion weighted imaging (DWI) findings of GS.

PMID: 25614846 [PubMed]

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Identification of a novel E-box binding PI polyamide inhibiting MYC-driven cell-proliferation.

Posted by rob on January 23, 2015 under Uncategorized | Comments are off for this article

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Identification of a novel E-box binding PI polyamide inhibiting MYC-driven cell-proliferation.

Cancer Sci. 2015 Jan 22;

Authors: Mishra R, Watanabe T, Kimura MT, Koshikawa N, Ikeda M, Uekusa S, Kawashima H, Wang X, Igarashi J, Choudhury D, Grandori C, Kemp CJ, Ohira M, Verma NK, Kobayashi Y, Takeuchi J, Koshinaga T, Nemoto N, Fukuda N, Soma M, Kusafuka T, Fujiwara K, Nagase H

Abstract

The MYC transcription factor plays a crucial role in the regulation of cell cycle progression, apoptosis, angiogenesis, and cellular transformation. Due to its oncogenic activities and over expression in a majority of human cancers, it is an interesting target for novel drug therapies. MYC binding to the E-box (5′-CACGTGT-3′) sequence at gene promoters contributes to more than 4,000 MYC-dependent transcripts. Owing to its importance in MYC regulation, we designed a novel sequence-specific DNA-binding Pyrrole-Imidazole (PI) polyamide, Myc-5, that recognizes E-box consensus sequence. Bioinformatics analysis revealed that Myc-5 binding sequence appeared in 5′ MYC binding E-box sequences at the eIF4G1, CCND1 and CDK4 gene promoters. Furthermore Chromatin immunoprecipitation (ChIP) coupled with detection by qPCR demonstrated that Myc-5 has the ability to inhibit MYC-binding at the target gene promoters and thus cause down-regulation at m-RNA level and protein expression of its target gene in human Burkitt’s lymphoma model cell line, P493.6, carrying an inducible MYC repression system and K562 (human chronic myelogenous leukaemia) cell lines. Single intravenous injection of Myc-5 at 7.5 mg/kg dose caused a significant tumor-growth inhibition in a MYC-dependent tumor xenograft model without evidence of toxicity. We report here a compelling rationale for the identification of a PI polyamide that inhibits a part of an E-box-mediated MYC downstream gene expression and is a model for showing that phenotype-associated MYC downstream gene targets consequently inhibits MYC dependent tumor growth. This article is protected by copyright. All rights reserved.

PMID: 25611295 [PubMed - as supplied by publisher]

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?-Hemoglobin-stabilizing Protein: An Effective Marker for Erythroid Precursors in Bone Marrow Biopsy Specimens.

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?-Hemoglobin-stabilizing Protein: An Effective Marker for Erythroid Precursors in Bone Marrow Biopsy Specimens.

Appl Immunohistochem Mol Morphol. 2015 Jan 21;

Authors: Yu H, Pinkus JL, Pinkus GS

Abstract

Accurate analysis of the erythroid lineage is essential in evaluating bone marrow biopsies and can be particularly challenging in settings of dyserythropoiesis. ?-Hemoglobin-stabilizing protein (AHSP) is an erythroid-specific chaperone protein and represents a potential specific marker for erythroid elements. This study defines the immunohistochemical profile of AHSP, as compared with an established erythroid marker CD71, in 101 bone marrow biopsies including normal marrows and cases of acute pure erythroid leukemia, acute erythroid/myeloid leukemia, other types of acute myeloid leukemia, myelodysplastic syndrome, chronic myelogenous leukemia, other types of myeloproliferative neoplasm, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, plasma cell neoplasm, and metastatic carcinoma. In acute pure erythroid leukemia, blasts in 7 of 11 cases showed similar reactivity for CD71 and AHSP, whereas less extensive reactivity was observed for AHSP as compared with CD71 in the remaining 4 cases. In normal marrows and other various disorders, reactivity for AHSP was similar to CD71 and was restricted to the erythroid lineage. Mature erythrocytes were negative for AHSP as were myeloblasts, lymphoblasts, nonerythroid hematopoietic marrow elements, plasma cells, and carcinoma cells. AHSP is an effective marker for detection of normal or abnormal erythroid precursors in bone marrow biopsies and is a useful addition to an immunohistochemical panel for assessment of neoplastic cells of possible erythroid derivation.

PMID: 25611244 [PubMed - as supplied by publisher]

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Antioxidant enzyme inhibitor role of phosphine metal complexes in lung and leukemia cell lines.

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Antioxidant enzyme inhibitor role of phosphine metal complexes in lung and leukemia cell lines.

Bioinorg Chem Appl. 2014;2014:717421

Authors: Sayg?de?er Demir B, Kele? T, Serinda? O

Abstract

Phosphine metal complexes have been recently evaluated in the field of cancer therapy. In this research, the cytotoxic effects of some metal phosphines {[PdCl2((CH2OH)2PCH2)2NCH3] (C1), [RuCl2(((CH2OH)2PCH2)2NCH3)2] (C2), [PtCl2((Ph2PCH2)2NCH3)(timin)2] (C3)} on K562 (human myelogenous leukemia cell line) and A549 (adenocarcinomic human alveolar basal epithelial cells) cells were investigated using the MTT test. C1 and C2 are water-soluble metal complexes, which may have some advantages in in vitro and in vivo studies. The effects of the above-mentioned metal complexes on thioredoxin reductase (TrxR) (EC: 1.8.1.9), glutathione peroxidase (GPx) (EC: 1.11.1.9), and catalase (Cat) (EC: 1.11.1.6) enzymes were also tested. The results of this research showed that all three metal complexes indicated dose-dependent cytotoxicity on A549 and K562 cell lines and that the complexes inhibited different percentages of the TrxR, GPx, and Cat enzymes of these tumor cells.

PMID: 25610346 [PubMed]

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DNMT3A mutational status affects the results of dose-escalated induction therapy in acute myelogenous leukemia.

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DNMT3A mutational status affects the results of dose-escalated induction therapy in acute myelogenous leukemia.

Clin Cancer Res. 2015 Jan 21;

Authors: Sehgal AR, Gimotty PA, Zhao J, Hsu JM, Daber R, Morrissette JD, Luger SM, Loren AW, Carroll M

Abstract

Purpose: DNA methyltransferase 3A (DNMT3A) is one of the commonly mutated genes in acute myelogenous leukemia (AML). Reports on the prognostic significance of DNMT3A mutations have been inconsistent, and most of the data is available only for patients 60 years of age or younger. We hypothesized that this inconsistency is due to an interaction between the dose of anthracycline used in induction therapy and DNMT3A status. We studied whether patients with DNMT3A-mutated AML treated with standard dose anthracyclines had an inferior survival compared to patients with other mutation profiles or those who received high dose therapy. Experimental design: 152 patients in this retrospective cohort study (median age, 54 years) with de-novo AML underwent induction therapy and next-generation sequencing of 33 commonly mutated genes in hematologic malignancies, including DNMT3A, FLT3-ITD, NPM1, and IDH1/2. Cox regression was used to if those with DNMT3A mutations who were treated with standard dose anthracycline had inferior survival. Results: DNMT3A mutations, found in 32% of patients, were not associated with an inferior survival. Dose escalation of anthracycline in the induction regimen was associated with improved survival in those with DNMT3A mutations but not those with wild-type DNMT3A. Patients with DNMT3A mutations who received standard dose induction had shorter survival time than other patient groups (10.1 months vs. 19.8 months, p=0.0129). This relationship remained significant (HR: 1.90, p=0.006) controlling for multiple variables. Conclusions: Patients with DNMT3A-mutated AML have an inferior survival when treated with standard-dose anthracycline induction therapy. This group should be considered for high-dose induction therapy.

PMID: 25609058 [PubMed - as supplied by publisher]

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Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival.

Posted by rob on January 21, 2015 under Uncategorized | Comments are off for this article

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Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival.

J Clin Invest. 2014 Sep 2;124(9):3847-62

Authors: Chen Y, Peng C, Abraham SA, Shan Y, Guo Z, Desouza N, Cheloni G, Li D, Holyoake TL, Li S

Abstract

Cancer stem cells (CSCs) are responsible for the initiation and maintenance of some types of cancer, suggesting that inhibition of these cells may limit disease progression and relapse. Unfortunately, few CSC-specific genes have been identified. Here, we determined that the gene encoding arachidonate 15-lipoxygenase (Alox15/15-LO) is essential for the survival of leukemia stem cells (LSCs) in a murine model of BCR-ABL-induced chronic myeloid leukemia (CML). In the absence of Alox15, BCR-ABL was unable to induce CML in mice. Furthermore, Alox15 deletion impaired LSC function by affecting cell division and apoptosis, leading to an eventual depletion of LSCs. Moreover, chemical inhibition of 15-LO function impaired LSC function and attenuated CML in mice. The defective CML phenotype in Alox15-deficient animals was rescued by depleting the gene encoding P-selectin, which is upregulated in Alox15-deficient animals. Both deletion and overexpression of P-selectin affected the survival of LSCs. In human CML cell lines and CD34+ cells, knockdown of Alox15 or inhibition of 15-LO dramatically reduced survival. Loss of Alox15 altered expression of PTEN, PI3K/AKT, and the transcription factor ICSBP, which are known mediators of cancer pathogenesis. These results suggest that ALOX15 has potential as a therapeutic target for eradicating LSCs in CML.

PMID: 25105362 [PubMed - indexed for MEDLINE]

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Pegylated gold nanoparticles induce apoptosis in human chronic myeloid leukemia cells.

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Pegylated gold nanoparticles induce apoptosis in human chronic myeloid leukemia cells.

Biomed Res Int. 2014;2014:182353

Authors: Huang YC, Yang YC, Yang KC, Shieh HR, Wang TY, Hwu Y, Chen YJ

Abstract

Gold nanoparticles (AuNPs) have several potential biological applications as well as excellent biocompatibility. AuNPs with surface modification using polyethylene glycol (PEG-AuNPs) can facilitate easy conjugation with various biological molecules of interest. To examine the anticancer bioactivity of PEG-AuNPs, we investigated their effect on human chronic myeloid leukemia K562 cells. The results indicated that PEG-AuNPs markedly inhibited the viability and impaired the cell membrane integrity of K562 cells. The particles caused morphological changes typical of cell death, and a marked increase in the sub-G1 population in DNA histogram, indicating apoptosis. In addition, PEG-AuNPs reduced the mitochondrial transmembrane potential, a hallmark of the involvement of intrinsic apoptotic pathway in K562 cells. Observation of ultrastructure under a transmission electron microscope revealed that the internalized PEG-AuNPs were distributed into cytoplasmic vacuoles and damaged mitochondria, and subsequently accumulated in areas surrounding the nuclear membrane. In conclusion, PEG-AuNPs may have the potential to inhibit growth and induce apoptosis in human chronic myeloid leukemia cells.

PMID: 24790990 [PubMed - indexed for MEDLINE]

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Safety and pharmacokinetics of S-1 in a recurrent colon cancer patient with chronic myeloid leukemia treated with dasatinib: a case report.

Posted by rob on January 20, 2015 under Uncategorized | Comments are off for this article

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Safety and pharmacokinetics of S-1 in a recurrent colon cancer patient with chronic myeloid leukemia treated with dasatinib: a case report.

Cancer Chemother Pharmacol. 2014 Dec;74(6):1321-4

Authors: Sueda T, Kudo T, Sakai D, Uemura M, Nishimura J, Hata T, Takemasa I, Mizushima T, Yamamoto H, Ezoe S, Matsumoto K, Doki Y, Mori M, Satoh T

Abstract

PURPOSE: The safety of S-1 in recurrent colorectal cancer patients with chronic myeloid leukemia (CML) treated with dasatinib has not been established. We evaluated the safety and pharmacokinetics of S-1 in a recurrent colon cancer patient with CML treated with dasatinib.

PATIENT: A 70-year-old man had undergone surgery three times for sigmoid colon cancer and recurrence. Systemic chemotherapy with S-1 plus oxaliplatin plus bevacizumab as a clinical trial had already been administered because of metastatic colon cancer. The patient’s medical history was CML, and he had been receiving dasatinib treatment (100 mg once daily). Based on the diagnosis of unresectable and multiple metastases, S-1 monotherapy was started. S-1 (120 mg/day) was taken for 28 consecutive days, followed by a 14-day rest. Blood samples were obtained before and after the first administration of S-1. The plasma pharmacokinetics of S-1 were comparable to a pharmacokinetics study of S-1.

RESULTS: The area under the plasma concentration-time curve (AUC0-8) of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), oxonate (Oxo), and 5-fluorouracil (5-FU) was 4,309.2, 716.3, 86.8, and 492.75 ng h/mL, respectively, after S-1 administration. The pharmacokinetics of FT, CDHP, Oxo, and 5-FU after treatment with S-1 were not significantly different from a phase I pharmacokinetics study of S-1. During treatment with S-1 and dasatinib, CML relapse and serious myelosuppression were not observed.

CONCLUSIONS: Our report suggests that S-1 is an important treatment option for recurrent colorectal cancer in patients with CML treated with dasatinib.

PMID: 25374410 [PubMed - indexed for MEDLINE]

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HIF-? Promotes Chronic Myelogenous Leukemia Cell Proliferation by Upregulating p21 Expression.

Posted by rob on January 19, 2015 under Uncategorized | Comments are off for this article

HIF-? Promotes Chronic Myelogenous Leukemia Cell Proliferation by Upregulating p21 Expression.

Cell Biochem Biophys. 2015 Jan 18;

Authors: Chen H, Shen Y, Gong F, Jiang Y, Zhang R

Abstract

We sought to determine the expression levels of hypoxia-inducible factor-1? (HIF-1?) in the bone marrow chronic myelogenous leukemia (CML) patients. We also tried to determine the roles HIF-1? in the proliferation of CML cells by small interfering RNA (siRNA) knockdown. Real-time PCR was performed to determine the expression levels of HIF-1? in the bone marrows of CML patients and healthy volunteers. HIF-1? knockdown by siRNA in K562 cells was confirmed by RT-PCR. Proliferation and colony formation of the treated cells were determined by CCK8 after HIF-1? knockdown. RT-PCR and western blotting were performed to detect mRNA and protein levels of p21 and p53 in K562 cells. HIF-1? mRNA expression in the bone marrow of CML patients was significantly higher than that in the control, which was statistically significant (P < 0.05). HIF-1? knockdown dramatically reduced the proliferation of K562 cells, which was also statistically significant (P < 0.05). HIF-1? knockdown markedly reduced the colony formation ability of K562 cells, which was also statistically significant (P < 0.05). The mRNA and protein expression of p21 were significantly reduced in K562 cell after HIF-1? knockdown with affecting the mRNA and protein levels of p53. HIF-? promotes chronic CML cell proliferation by up-regulating p21 expression.

PMID: 25596666 [PubMed - as supplied by publisher]

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Mechanism of synergy of BH3 mimetics and paclitaxel in chronic myeloid leukemia cells: Mcl-1 inhibition.

Posted by rob on January 18, 2015 under Uncategorized | Comments are off for this article

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Mechanism of synergy of BH3 mimetics and paclitaxel in chronic myeloid leukemia cells: Mcl-1 inhibition.

Eur J Pharm Sci. 2015 Jan 14;

Authors: Song T, Sheng H, Liu Y, Xie M, Chen Q, Yu X, Chai G, Zhang Z

Abstract

Paclitaxel is an alternative chemotherapeutic agent for chronic myelogenous leukemia (CML) when primary or secondary resistance of tyrosine kinase inhibitors (TKI) is emerging, because paclitaxel could bypass the apoptotic deficiencies linked to p53 and fas ligand pathways in CML. However, high levels of Bcl-2 family proteins in CML could resist paclitaxel-induced apoptosis. Herein, we utilized two BH3 mimetics ABT-737 and S1 to study the potential of BH3 mimetics in combination with paclitaxel in treatment of CML cells and illustrated the mechanism by which BH3 mimetics synergize with paclitaxel. As a single agent, S1 could induce apoptosis in CML-derived cell line K562, whereas ABT-737 was largely ineffective. However, both of the two agents could efficiently synergize with paclitaxel through intrinsic apoptosis pathway. By using Bcl-2 siRNA, Bcl-XL siRNA or Mcl-1 siRNA, we found although each of the three members exhibited activities to block paclitaxel-induced apoptosis, Mcl-1 was the determinant for the synergistic effect between paclitaxel and ABT-737 or S1. Furthermore, paclitaxel/ABT737 synergized to drastically upregulate Bim to displace Bak from Mcl-1, whereas S1 directly binds Mcl-1 to release both Bim and Bak. As such, ABT-737 and S1 sensitized CML to paclitaxel by Mcl-1 inhibition, indirect inhibition through Bim antagonizing Mcl-1, or direct inhibition through binding to Mcl-1 itself. Finally, activation of JNK/Bim pathway was identified as the apical mechanism for ABT-737/paclitaxel synergism. Together, our results demonstrated potent synergy between BH3 mimetics and paclitaxel in the killing of CML cells and revealed an important role for Mcl-1 in mediating synergism by these agents.

PMID: 25596561 [PubMed - as supplied by publisher]

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Chryseobacterium indologenes in a woman with acute leukemia in Senegal: a case report.

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Chryseobacterium indologenes in a woman with acute leukemia in Senegal: a case report.

J Med Case Rep. 2014;8:138

Authors: Omar A, Camara M, Fall S, Ngom-Cisse S, Fall B, Ba-Diallo A, Diop-Ndiaye H, Toure-Kane C, Mboup S, Gaye-Diallo A

Abstract

INTRODUCTION: This report documents a rare case of Chryseobacterium indologenes urinary tract infection in Senegal. Chryseobacterium indologenes is an uncommon human pathogen reported in hospital outbreaks in Taiwan and there have been some sporadic cases reported in Europe and in the USA mainly from immune-suppressed patients.

CASE PRESENTATION: This case report describes a 42-year-old woman of Wolofa ethnicity who was hospitalized in our Department of Internal Medicine in a Senegalese university teaching hospital, with acute leukemia who died of severe sepsis 10 days following her hospitalization. A strain of Chryseobacterium indologenes isolated from her urine sample was resistant to several beta-lactams including ampicillin (minimum inhibitory concentrations ? 256 ?g/mL), cefotaxime (minimum inhibitory concentrations 32 ?g/mL) and imipenem (minimum inhibitory concentrations ? 32 ?g/mL), whereas it was susceptible to piperacillin (minimum inhibitory concentrations 16 ?g/mL), cefepime (minimum inhibitory concentrations 4 ?g/mL), ceftazidime (minimum inhibitory concentrations 4 ?g/mL), trimethoprim-sulfamethoxazole (minimum inhibitory concentrations ? 0.25 ?g/mL) and all tested quinolones including nalidixic acid (minimum inhibitory concentrations ? 2 ?g/mL).

CONCLUSIONS: Chryseobacterium indologenes although uncommon, is an important pathogen causing infection in hospitalized patients. The management of this infection needs better identification, drug susceptibility testing and monitoring of immunosuppressed patients with long hospitalizations.

PMID: 24886628 [PubMed - indexed for MEDLINE]

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Evolutionarily Conserved Signaling Pathways: Acting in the Shadows of Acute Myelogenous Leukemia’s Genetic Diversity.

Posted by rob on January 17, 2015 under Uncategorized | Comments are off for this article

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Evolutionarily Conserved Signaling Pathways: Acting in the Shadows of Acute Myelogenous Leukemia’s Genetic Diversity.

Clin Cancer Res. 2015 Jan 15;21(2):240-248

Authors: Heidel FH, Arreba-Tutusaus P, Armstrong SA, Fischer T

Abstract

Acute myelogenous leukemia stem cells (AML-LSC) give rise to the leukemic bulk population and maintain disease. Relapse can arise from residual LSCs that have distinct sensitivity and dependencies when compared with the AML bulk. AML-LSCs are driven by genetic and epigenomic changes, and these alterations influence prognosis and clonal selection. Therapies targeting these molecular aberrations have been developed and show promising responses in advanced clinical trials; however, so far success with LSCs has been limited. Besides the genetic diversity, AML-LSCs are critically influenced by the microenvironment, and a third crucial aspect has recently come to the fore: A group of evolutionarily conserved signaling pathways such as canonical Wnt signaling, Notch signaling, or the Hedgehog pathway can be essential for maintenance of AML-LSC but may be redundant for normal hematopoietic stem cells. In addition, early reports suggest also regulators of cell polarity may also influence hematopoietic stem cells and AML biology. Interactions between these pathways have been investigated recently and suggest a network of signaling pathways involved in regulation of self-renewal and response to oncogenic stress. Here, we review how recent discoveries on regulation of AML-LSC-relevant evolutionarily conserved pathways may open opportunities for novel treatment approaches eradicating residual disease. Clin Cancer Res; 21(2); 240-8. ©2015 AACR.

PMID: 25593343 [PubMed - as supplied by publisher]

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Population pharmacokinetics and individualized dosage prediction of cyclosporine in allogeneic hematopoietic stem cell transplant patients.

Posted by rob on January 16, 2015 under Uncategorized | Comments are off for this article

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Population pharmacokinetics and individualized dosage prediction of cyclosporine in allogeneic hematopoietic stem cell transplant patients.

Am J Med Sci. 2014 Dec;348(6):448-54

Authors: Xue L, Zhang WW, Ding XL, Zhang JJ, Bao JA, Miao LY

Abstract

BACKGROUND: Cyclosporine (CsA), a potent immunosuppressive agent used to prevent rejection, is characterized by large individual variability. The purpose of this study was to explore the pharmacokinetic characteristics of CsA and establish a CsA population pharmacokinetic model that could be used for personalized therapy in allogeneic hematopoietic stem cell transplant (allo-HSCT) patients.

METHODS: Clinical data were obtained from 117 allo-HSCT patients. The data analysis was performed using NONMEM software. A first-order conditional estimation with interaction (FOCE-I) method within NONMEM was used to estimate the parameters. The covariates, including demographics, hematological indices, biochemical levels, concurrent drugs, and genetic polymorphisms of CYP3A4, CYP3A5, and ABCB1, were evaluated quantitatively. The stability of the final model was validated by a nonparametric bootstrap procedure.

RESULTS: A total of 1,571 observed concentrations were collected. A 1-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL), volume of distribution (V), and bioavailability were 29.6 L/hr, 605 L, and 0.619, respectively. The interindividual variability of these parameters was 20.4, 66.1, and 30.4%, respectively. The residual error was 31.4% and 23.7 ng/mL. The duration of CsA therapy, hematocrit, antifungal agent administration, triglycerides, and weight were identified as the main covariates that influenced CL, and hematocrit had a significant effect on V. The internal validation showed that the final model was stable and accurate.

CONCLUSIONS: This study established a population pharmacokinetic model of CsA in allo-HSCT patients that could provide the foundation for personalized use of CsA in the clinic.

PMID: 25247760 [PubMed - indexed for MEDLINE]

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Long-term imatinib treatment does not cause testicular toxicity in male adolescents with chronic myeloid leukemia and in a juvenile rat model.

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Long-term imatinib treatment does not cause testicular toxicity in male adolescents with chronic myeloid leukemia and in a juvenile rat model.

Klin Padiatr. 2014 May;226(3):169-74

Authors: Tauer JT, Ulmer A, Glauche I, Jung R, Suttorp M

Abstract

BACKGROUND: The impact of exposure to the tyrosine kinase inhibitor (TKI) imatinib (IMA) on the male reproductive endocrine system is still discussed controversially. We therefore investigated testosterone (Testo) and inhibin B (InB) in blood serum from male adolescents with chronic myeloid leukemia (CML) under long-term TKI treatment. Also long-term exposure to TKIs was studied in a juvenile rat model.

METHODS: Serum was collected at 3 months intervals from 13 boys (age: 7.8-18.9 years, median: 12.8 years) with CML receiving TKI treatment over 3-58 months (median: 18 months). 4 weeks (w) old male rats were exposed, either chronically or intermittently, via the drinking water to a standard (SD) and a high dose (=2-fold SD) of IMA, dasatinib (DASA), or bosutinib (BOSU) over a 10?w period. Controls received water only. Animals were sacrificed after 2?w (prepubertal), 4?w (pubertal), and 10?w (postpubertal) of exposure. Testo and InB serum levels were measured by ELISA.

RESULTS: Boys exhibited Testo and InB levels within normal age-related reference ranges and no pattern of rising or falling levels during TKI treatment could be observed. In rats, Testo levels under IMA exposure tended to be non-significantly lowered at postpubertal age compared to controls while no significant differences were found under DASA and BOSU exposure. Animals’ InB levels did not significantly differ from controls for all TKIs, at all doses, and by all application schemes tested.

CONCLUSION: With the limitation that the number of individuals tested was rather small, testicular toxicity due to TKI seems unlikely as no alterations of Testo and InB blood levels neither in male adolescent patients nor in rats under long-term TKI exposure was observed.

PMID: 24819387 [PubMed - indexed for MEDLINE]

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The Effects of Extending of Co-planarity in a Series of Structurally Relative Polypyridyl Palladium(II) Complexes on DNA-binding and Cytotoxicity Properties.

Posted by rob on January 15, 2015 under Uncategorized | Comments are off for this article

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The Effects of Extending of Co-planarity in a Series of Structurally Relative Polypyridyl Palladium(II) Complexes on DNA-binding and Cytotoxicity Properties.

Iran J Pharm Res. 2014;13(4):1279-94

Authors: Shahraki S, Mansouri-Torshizi H, Sori Nezami Z, Ghahghaei A, Yaghoubi F, Divsalar A, Saboury AA, H Shirazi F

Abstract

In depth interaction studies between calf thymus deoxyribonucleic acid (CT-DNA) and a series of four structurally relative palladium(II) complexes [Pd(en)(HB)](NO3)2 (a-d), where en is ethylenediamine and heterocyclic base (HB) is 2,2′-bipyridine (bpy, a); 1,10-phenanthroline (phen, b); dipyridoquinoxaline (dpq, c) and dipyridophenazine (dppz, d) (Figure 1), were performed. These studies have been investigated by utilizing the electronic absorption spectroscopy, fluorescence spectra and ethidium bromide (EBr) displacement and gel filtration techniques. a-d complexes cooperatively bind and denature the DNA at low concentrations. Their concentration at midpoint of transition, L1/2, follows the order a >> b > c > d. Also the g, the number of binding sites per 1000 nucleotides, follows the order a >> b ~ c > d. EBr and Scatchard experiments for a-d complexes suggest efficient intercalative binding affinity to CT-DNA giving the order: d > c > b > a. Several binding and thermodynamic parameters are also described. The biological activity of these cationic and water soluble palladium complexes were tested against chronic myelogenous leukemia cell line, K562. b, c and d complexes show cytotoxic concentration (Cc50) values much lower than cisplatin.

PMID: 25587317 [PubMed]

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Phenethyl isothiocyanate inhibits growth of human chronic myeloid leukemia K562 cells via reactive oxygen species generation and caspases.

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Phenethyl isothiocyanate inhibits growth of human chronic myeloid leukemia K562 cells via reactive oxygen species generation and caspases.

Mol Med Rep. 2014 Jul;10(1):543-9

Authors: Wang Y, Wei S, Wang J, Fang Q, Chai Q

Abstract

Phenethyl isothiocyanate (PEITC), a potential cancer chemopreventive constituent of cruciferous vegetables, including watercress, has been reported to inhibit cancer cell growth by arresting the cell cycle and inducing apoptosis in various human cancer cell models. However, the role of PEITC in the inhibition of human chronic myeloid leukemia (CML) K562 cell growth and its underlying mechanisms have yet to be elucidated. In the present study, PEITC was found to induce cell death through the induction of reactive oxygen species (ROS) stress and oxidative damage. Heme oxygenase?1 (HO?1), which participates in the development of numerous tumors and the sensitivity of these tumors to chemotherapeutic drugs, plays a protective role by modulating oxidative injury. Therefore, the present study assessed the inhibitory effect of PEITC on K562 cells and whether HO?1 facilitated cell apoptosis and ROS generation. PEITC was found to suppress cell growth and cause apoptosis by promoting Fas and Fas ligand expression, increasing ROS generation and by the successive release of cytochrome c as well as the activation of caspase?9 and caspase?3. PEITC was also combined with the HO?1 inhibitor zinc protoporphyrin IX and the inducer hemin to assess whether HO?1 determines cell survival and ROS generation. The results of the present study suggest that PEITC may be a potential anti?tumor compound for CML therapy, and that HO?1 has a critical function in PEITC?induced apoptosis and ROS generation.

PMID: 24788892 [PubMed - indexed for MEDLINE]

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In silico identification of novel kinase inhibitors targeting wild-type and T315I mutant ABL1 from FDA-approved drugs.

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In silico identification of novel kinase inhibitors targeting wild-type and T315I mutant ABL1 from FDA-approved drugs.

Mol Biosyst. 2014 Jun;10(6):1524-37

Authors: Xu HL, Wang ZJ, Liang XM, Li X, Shi Z, Zhou N, Bao JK

Abstract

The constitutively active fusion protein BCR-ABL1 is the major cause of chronic myeloid leukemia (CML), and selective inhibition of ABL1 is a promising approach for the treatment of CML. Reported drugs worked well in clinical practice, such as imatinib, dasatinib, nilotinib and bosutinib. However, resistance arises due to ABL1 mutation in patients, especially the T315I gate-keeper mutation. Thus, wide spectrum drugs targeting ABL1 are urgently needed. In order to screen potential drugs targeting wild-type ABL1 and T315I mutant ABL1, 1408 FDA approved small molecule drugs were subjected to molecular docking. With subsequent molecular dynamic (MD) simulation and MM/GBSA binding free energy calculation and energy decomposition, we identified chlorhexidine and sorafenib as potential “new use” drugs targeting wild-type ABL1, while nicergoline and plerixafor targeted T315I ABL1. Meanwhile, we also found that residues located in the ATP-binding site and A-loop motif played key roles in drug discovery towards ABL1. These findings may not only serve as a paradigm for the repositioning of existing approved drugs, but also instill new vitality to ABL1-targeted anti-CML therapeutics.

PMID: 24691568 [PubMed - indexed for MEDLINE]

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EAPB0503, a novel imidazoquinoxaline derivative, inhibits growth and induces apoptosis in chronic myeloid leukemia cells.

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EAPB0503, a novel imidazoquinoxaline derivative, inhibits growth and induces apoptosis in chronic myeloid leukemia cells.

Anticancer Drugs. 2014 Jul;25(6):624-32

Authors: Saliba J, Deleuze-Masquéfa C, Iskandarani A, El Eit R, Hmadi R, Mahon FX, Bazarbachi A, Bonnet PA, Nasr R

Abstract

Imatinib, the first-generation tyrosine kinase inhibitor, revolutionized the therapeutic management of chronic myeloid leukemia (CML) and is highly effective in inducing remissions and prolonging the survival of CML patients. However, one-third of patients develop intolerance or resistance to treatment, and CML stem cells remain insensitive to this therapy, leading almost inevitably to relapse upon treatment discontinuation. Imidazoquinoxalines are imiquimod derivatives that induce growth inhibition and induction of caspase-dependent apoptosis in melanoma and T-cell lymphoma cells. We investigated the effects of EAPB0203 and EAPB0503, two novel imidazoquinoxaline derivatives, on human CML cell lines and showed that they induced a dose-dependent and time-dependent cell growth inhibition. EAPB0503 proved more potent and induced a specific cell cycle arrest in mitosis in CML cells and direct activation of apoptosis as evidenced by increased pre-G0 population, breakdown of mitochondrial membrane potential, PARP cleavage, and DNA breakage. Interestingly, EAPB0503 decreased BCR-ABL oncoprotein levels. The combination of EAPB0503 with imatinib synergized to inhibit the proliferation of CML cells, and most importantly, EABP0503 inhibited the proliferation of imatinib-resistant CML cells, offering promising therapeutic modalities that would circumvent resistance to tyrosine kinase inhibitors and improve the prognosis of CML.

PMID: 24463483 [PubMed - indexed for MEDLINE]

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Health-related quality of life of patients with newly diagnosed chronic myeloid leukemia treated with allogeneic hematopoietic SCT versus imatinib.

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Health-related quality of life of patients with newly diagnosed chronic myeloid leukemia treated with allogeneic hematopoietic SCT versus imatinib.

Bone Marrow Transplant. 2014 Apr;49(4):576-80

Authors: Mo XD, Jiang Q, Xu LP, Liu DH, Liu KY, Jiang B, Jiang H, Chen H, Chen YH, Zhang XH, Han W, Wang Y, Huang XJ

Abstract

To evaluate and compare the health-related quality of life (HRQOL) of patients with newly diagnosed CML in the first chronic phase (CML-CP1) receiving HLA-identical sibling donor (ISD) hematopoietic SCT (HSCT) or imatinib, a cross-sectional study that was part of a prospective cohort study at the Institute of Hematology, Peking University was performed. A total of 222 patients including 126 and 96 in the imatinib and ISD HSCT groups, respectively, were enrolled. HRQOL was measured using the Medical Outcomes Study 36-Item Short-Form Health Survey. The ISD HSCT group functioned significantly better on the role-physical functioning and mental health subscales, as well as the mental component summary (MCS) than the imatinib group. HRQOL was generally comparable to groups in the young population. Multivariate analysis showed that white blood cell count ? 30 × 10(9)/L and plts count ? 450 × 10(9)/L were the major adverse factors affecting HRQOL in long-term survivors. Imatinib therapy was also an adverse factor affecting the MCS (odds ratio=1.7, P=0.032). Thus, long-term CML-CP1 survivors receiving ISD HSCT can attain desirable HRQOL comparable to or better than that of patients receiving imatinib.

PMID: 24442252 [PubMed - indexed for MEDLINE]

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