Posted by rob on May 31, 2010 under Uncategorized | 
Escin, a pentacyclic triterpene, chemosensitizes human tumor cells through inhibition of nuclear factor-kappaB signaling pathway.
Mol Pharmacol. 2010 May;77(5):818-27
Authors: Harikumar KB, Sung B, Pandey MK, Guha S, Krishnan S, Aggarwal BB
Agents that can enhance tumor cell apoptosis and inhibit invasion have potential for the treatment of cancer. Here, we report the identification of escin, a pentacyclic triterpenoid from horse chestnut that exhibits antitumor potential against leukemia and multiple myeloma. Whether examined by esterase staining, phosphatidyl-serine staining, DNA breakage, or caspase-mediated poly(ADP-ribose) polymerase cleavage, escin potentiated tumor necrosis factor (TNF)-induced apoptosis but inhibited tumor cell invasion. This correlated with the down-regulation of bcl-2, cellular inhibitor of apoptosis protein-2, cyclin D1, cyclooxygenase-2, intercellular adhesion molecule-1, matrix metalloproteinase-9, and vascular endothelial growth factor, which are all regulated by the activation of the transcription factor NF-kappaB. When examined by electrophoretic mobility shift assay, the triterpenoid suppressed nuclear factor-kappaB (NF-kappaB) activation induced by TNF and other inflammatory agents, and this correlated with the inhibition of IkappaBalpha phosphorylation and degradation, inhibition of IkappaB kinase complex (IKK) activation, suppression of p65 phosphorylation and nuclear translocation, and abrogation of NF-kappaB-dependent reporter activity. Overall, our results demonstrate that escin inhibits activation of NF-kappaB through inhibition of IKK, leading to down-regulation of NF-kappaB-regulated cell survival and metastatic gene products and thus resulting in sensitization of cells to cytokines and chemotherapeutic agents.
PMID: 20103608 [PubMed - indexed for MEDLINE]
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Abstract We investigated the efficacy of the induction therapy involving granulocyte colony-stimulating factor (G-CSF) and low-dose
homoharringtonine as well as standard-dose imatinib, which we called the G-CSF?+?homoharringtonine?+?imatinib (GHI) regimen,
in patients with chronic myelogenous leukemia (CML) in blast crisis who have failed prior single-agent therapy with imatinib.
Twelve patients were enrolled. The GHI regimen consisted in a unique induction course where imatinib was administered at 400 mg day?1 until remission, together with homoharringtonine (1 mg/m2?s.c. twice daily for 14 days every 28 days), and G-CSF, which was administered 1 day before chemotherapy (5 µg/kg s.c. daily).
Patients who failed to obtain …
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Posted by rob on May 21, 2010 under Uncategorized |
Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia.
J Clin Invest. 2010 May 17;
Authors: Xiang Z, Luo H, Payton JE, Cain J, Ley TJ, Opferman JT, Tomasson MH
Antiapoptotic BCL2 family members have been implicated in the pathogenesis of acute myelogenous leukemia (AML), but the functional significance and relative importance of individual proteins (e.g., BCL2, BCL-XL, and myeloid cell leukemia 1 [MCL1]) remain poorly understood. Here, we examined the expression of BCL2, BCL-XL, and MCL1 in primary human hematopoietic subsets and leukemic blasts from AML patients and found that MCL1 transcripts were consistently expressed at high levels in all samples tested. Consistent with this, Mcl1 protein was also highly expressed in myeloid leukemic blasts in a mouse Myc-induced model of AML. We used this model to test the hypothesis that Mcl1 facilitates AML development by allowing myeloid progenitor cells to evade Myc-induced cell death. Indeed, activation of Myc for 7 days in vivo substantially increased myeloid lineage cell numbers, whereas hematopoietic stem, progenitor, and B-lineage cells were depleted. Furthermore, Mcl1 haploinsufficiency abrogated AML development. In addition, deletion of a single allele of Mcl1 from fully transformed AML cells substantially prolonged the survival of transplanted mice. Conversely, the rapid lethality of disease was restored by coexpression of Bcl2 and Myc in Mcl1-haploinsufficient cells. Together, these data demonstrate a critical and dose-dependent role for Mcl1 in AML pathogenesis in mice and suggest that MCL1 may be a promising therapeutic target in patients with de novo AML.
PMID: 20484815 [PubMed - as supplied by publisher]
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Pristimerin induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation by blocking NF-kappaB signaling and depleting Bcr-Abl.
Mol Cancer. 2010 May 19;9(1):112
Authors: Lu Z, Jin Y, Chen C, Li J, Cao Q, Pan J
ABSTRACT: BACKGROUND: Chronic myelogenous leukemia (CML) is characterized by the chimeric tyrosine kinase Bcr-Abl. Bcr-Abl-T315I is the notorious point mutation that causes resistance to imatinib and the second generation tyrosine kinase inhibitors, leading to poor prognosis. CML blasts have constitutive p65 (RelA NF-kappaB) transcriptional activity, and NF-kappaB may be a potential target for molecular therapies in CML that may also be effective against CML cells with Bcr-Abl-T315I. RESULTS: In this report, we discovered that pristimerin, a quinonemethide triterpenoid isolated from Celastraceae and Hippocrateaceae, inhibited growth and induced apoptosis in CML cells, including the cells harboring Bcr-Abl-T315I mutation. Additionally, pristimerin inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Pristimerin blocked the TNFalpha-induced IkappaBalpha phosphorylation, translocation of p65, and expression of NF-kappaB-regulated genes. Pristimerin inhibited two steps in NF-kappaB signaling: TAK1-IKK and IKK-IkappaBalpha. Pristimerin potently inhibited two pairs of CML cell lines (KBM5 versus KBM5-T315I, 32D-Bcr-Abl versus 32D-Bcr-Abl-T315I) and primary cells from a CML patient with acquired resistance to imatinib. The mRNA and protein levels of Bcr-Abl in imatinib-sensitive (KBM5) or imatinib-resistant (KBM5-T315I) CML cells were reduced after pristimerin treatment. Further, inactivation of Bcr-Abl by imatinib pretreatment did not abrogate the TNFalpha-induced NF-kappaB activation while silencing p65 by siRNA did not affect the levels of Bcr-Abl, both results together indicating that NF-kappaB inactivation and Bcr-Abl inhibition may be parallel independent pathways. CONCLUSION: To our knowledge, this is the first report to show that pristimerin is effective in vitro and in vivo against CML cells, including those with the T315I mutation. The mechanisms may involve inhibition of NF-kappaB and Bcr-Abl. We concluded that pristimerin could be a lead compound for further drug development to overcome imatinib resistance in CML patients.
PMID: 20482842 [PubMed - as supplied by publisher]
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Analysis of Ikaros family splicing variants in human hematopoietic lineages.
Coll Antropol. 2010 Mar;34(1):59-62
Authors: MatuliÄ? M, Paradzik M, PuskariÄ? BJ, StipiÄ? J, Antica M
Transcription factors from the Ikaros family are involved in lymphocyte differentiation and have a critical role at specific check points of the haemopoietic pathway. However, how developmentally regulated changes are reflected in gene expression programs of lymphocyte differentiation is not well understood. It has been suggested that disregulation of transcription factors from the Ikaros family is associated with the development of different human leukemias. In this work we analyzed the state of Ikaros family members in different leukemic cells with the aim to explore the transcriptional control of human hematopoietic lineages and shed some new light on our understanding of transcription factor significance in human leukemias. By means of RT-PCR and specific primers we investigated the expression of Ikaros, Aiolos and Helios transcription factors and their splicing variants in seven leukemia cell lines derived from different types of leukemia (ALL, CML, AML) and lymphoma (histiocytic lymphoma, Burkitt lymphoma and anaplastic large cell lymphoma). In all of the cell lines examined Ikaros was present in dominant Ik1 to Ik4 isoforms and small Ik6 isoform was absent. Aiolos was expressed in the majority of the cell lines, of both, B and T origin, in the form of the full length Aio1. Helios was also present only in two long isoforms Hel1 and Hel2, and was absent in one third of the lines. Similar distribution of positive and negative expression of Aiolos and Helios found in various types of leukemias could implicate common pathways of their regulation.
PMID: 20432734 [PubMed - indexed for MEDLINE]
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Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib.
J Clin Oncol. 2010 May 10;28(14):2381-8
Authors: Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, Apperley JF, Szydlo R, Desai R, Kozlowski K, Paliompeis C, Latham V, Foroni L, Molimard M, Reid A, Rezvani K, de Lavallade H, Guallar C, Goldman J, Khorashad JS
PURPOSE: There is a considerable variability in the level of molecular responses achieved with imatinib therapy in patients with chronic myeloid leukemia (CML). These differences could result from variable therapy adherence. METHODS: Eighty-seven patients with chronic-phase CML treated with imatinib 400 mg/d for a median of 59.7 months (range, 25 to 104 months) who had achieved complete cytogenetic response had adherence monitored during a 3-month period by using a microelectronic monitoring device. Adherence was correlated with levels of molecular response. Other factors that could influence outcome were also analyzed. RESULTS: Median adherence rate was 98% (range, 24% to 104%). Twenty-three patients (26.4%) had adherence <or= 90%; in 12 of these patients (14%), adherence was <or= 80%. There was a strong correlation between adherence rate (<or= 90% or > 90%) and the 6-year probability of a 3-log reduction (also known as major molecular response [MMR]) in BCR-ABL1 transcripts (28.4% v 94.5%; P < .001) and also complete molecular response (CMR; 0% v 43.8%; P = .002). Multivariate analysis identified adherence (relative risk [RR], 11.7; P = .001) and expression of the molecular human organic cation transporter-1 (RR, 1.79; P = .038) as the only independent predictors for MMR. Adherence was the only independent predictor for CMR. No molecular responses were observed when adherence was <or= 80% (P < .001). Patients whose imatinib doses were increased had poor adherence (86.4%). In this latter population, adherence was the only independent predictor for inability to achieve an MMR (RR, 17.66; P = .006). CONCLUSION: In patients with CML treated with imatinib for some years, poor adherence may be the predominant reason for inability to obtain adequate molecular responses.
PMID: 20385986 [PubMed - indexed for MEDLINE]
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Counterpoint: Data first.
Nature. 2010 Apr 1;464(7289):679
Authors: Golub T
PMID: 20360719 [PubMed - indexed for MEDLINE]
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Sequential treatment with flavopiridol synergistically enhances pyrrolo-1,5-benzoxazepine-induced apoptosis in human chronic myeloid leukaemia cells including those resistant to imatinib treatment.
Biochem Pharmacol. 2010 Jul 1;80(1):31-8
Authors: Bright SA, Campiani G, Deininger MW, Lawler M, Williams DC, Zisterer DM
The Bcr-Abl kinase inhibitor, imatinib mesylate, is the front line treatment for chronic myeloid leukaemia (CML), but the emergence of imatinib resistance has led to the search for alternative drug treatments and the examination of combination therapies to overcome imatinib resistance. The pro-apoptotic PBOX compounds are a recently developed novel series of microtubule targeting agents (MTAs) that depolymerise tubulin. Recent data demonstrating enhanced MTA-induced tumour cell apoptosis upon combination with the cyclin dependent kinase (CDK)-1 inhibitor flavopiridol prompted us to examine whether this compound could similarly enhance the effect of the PBOX compounds. We thus characterised the apoptotic and cell cycle events associated with combination therapy of the PBOX compounds and flavopiridol and results showed a sequence dependent, synergistic enhancement of apoptosis in CML cells including those expressing the imatinib-resistant T315I mutant. Flavopiridol reduced the number of polyploid cells formed in response to PBOX treatment but only to a small extent, suggesting that inhibition of endoreplication was unlikely to play a major role in the mechanism by which flavopiridol synergistically enhanced PBOX-induced apoptosis. The addition of flavopiridol following PBOX-6 treatment did however result in an accelerated exit from the G2/M transition accompanied by an enhanced downregulation and deactivation of the CDK1/cyclin B1 complex and an enhanced degradation of the inhibitor of apoptosis protein (IAP) survivin. In conclusion, results from this study highlight the potential of these novel series of PBOX compounds, alone or in sequential combination with flavopiridol, as an effective therapy against CML.
PMID: 20206141 [PubMed - indexed for MEDLINE]
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Palmitoylation of oncogenic NRAS is essential for leukemogenesis.
Blood. 2010 Apr 29;115(17):3598-605
Authors: Cuiffo B, Ren R
Activating mutations of NRAS are common in acute myeloid leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. Like all RAS proteins, NRAS must undergo a series of post-translational modifications for differential targeting to distinct membrane subdomains. Although farnesylation is the obligatory first step in post-translational modifications of RAS, to date, successes of therapies targeting farnesyl protein transferase are modest. Other RAS modifications, such as palmitoylation, are required for optimal plasma membrane association of RAS proteins. However, the relative importance of these latter modifications of RAS in leukemogenesis is not clear. We have previously shown that expression of oncogenic NRAS using a bone marrow transduction and transplantation model efficiently induces a chronic myelomonocytic leukemia- or acute myeloid leukemia-like disease in mice. Here we examined the role of palmitoylation in NRAS leukemogenesis using this model. We found that palmitoylation is essential for leukemogenesis by oncogenic NRAS. We also found that farnesylation is essential for NRAS leukemogenesis, yet through a different mechanism from that of palmitoylation deficiency. This study demonstrates, for the first time, that palmitoylation is an essential process for NRAS leukemogenesis and suggests that the development of therapies targeting RAS palmitoylation may be effective in treating oncogenic NRAS-associated malignancies.
PMID: 20200357 [PubMed - indexed for MEDLINE]
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Nilotinib does not significantly reduce imatinib OCT-1 activity in either cell lines or primary CML cells.
Leukemia. 2010 Apr;24(4):855-7
Authors: Eadie L, Hughes TP, White DL
PMID: 20147980 [PubMed - indexed for MEDLINE]
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Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias.
Leukemia. 2010 Apr;24(4):671-8
Authors: Moore AS, Blagg J, Linardopoulos S, Pearson AD
Aurora kinases are a family of protein kinases that have a key role in multiple stages of mitosis. Over-expression of Aurora kinases, particularly Aurora A, has been demonstrated in a number of solid tumors and hematological malignancies. Not surprisingly, these serine/threonine kinases have become attractive small molecule targets for cancer therapeutics, with several inhibitors currently in early-phase clinical trials. A small number of compounds developed to date are highly selective for either Aurora A or Aurora B, while the majority inhibit both Aurora A and Aurora B; many of these compounds exhibit ‘off-target’ inhibition of kinases such as ABL, JAK2 and FLT3. It is currently unclear whether the therapeutic activity of these compounds in leukemia is primarily due to selective Aurora or multi-kinase inhibition. The most promising application for Aurora kinase inhibitors to date appears to be in FLT3-mutated acute myeloid leukemia (AML) and imatinib-resistant chronic myeloid leukemia/Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia, particularly when caused by the T315I mutation. Here we review the growing body of evidence supporting the use of Aurora kinase inhibitors as effective agents for AML and Ph+ leukemias.
PMID: 20147976 [PubMed - indexed for MEDLINE]
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Chronic myeloid leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 activity.
Leukemia. 2010 Apr;24(4):765-70
Authors: Engler JR, Frede A, Saunders VA, Zannettino AC, Hughes TP, White DL
Active influx of imatinib in chronic myeloid leukemia (CML) cells is mediated by the organic cation transporter 1 (OCT-1). Functional activity of OCT-1 (OCT-1 Activity) in mononuclear cells is an excellent predictor of molecular response over the first 24 months of imatinib therapy for chronic phase patients. CML progenitor cells are less sensitive to imatinib-induced apoptosis and are likely contributors to disease persistence. We investigated whether alterations in the expression and function of OCT-1 have a role in imatinib resistance in progenitors. We found the intracellular uptake and retention (IUR) of imatinib, OCT-1 Activity and OCT-1 mRNA expression are all significantly lower in CML CD34+ cells compared with mature CD34- cells (P<0.001). However, no differences in IUR or OCT-1 Activity were observed between these subsets in healthy donors. In contrast to OCT-1, ABCB1 and ABCG2 seemed to have no functional role in the transport of imatinib in CML CD34+ cells. Consistent with the observation that nilotinib uptake is not OCT-1 dependent, the IUR of nilotinib did not differ between CML CD34+ and CD34- cells. These results indicate that low imatinib accumulation in primitive CML cells, mediated through reduced OCT-1 Activity may be a critical determinant of long-term disease persistence.
PMID: 20147974 [PubMed - indexed for MEDLINE]
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Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors.
Leukemia. 2010 Apr;24(4):771-8
Authors: Hiwase DK, White DL, Powell JA, Saunders VA, Zrim SA, Frede AK, Guthridge MA, Lopez AF, D’Andrea RJ, To LB, Melo JV, Kumar S, Hughes TP
In chronic myeloid leukemia (CML) cell lines, brief exposure to pharmacologically relevant dasatinib concentrations results in apoptosis. In this study, we assess the impact of intensity and duration of Bcr-Abl kinase inhibition on primary CD34(+) progenitors of chronic phase CML patients. As CML cells exposed to dasatinib in vivo are in a cytokine-rich environment, we also assessed the effect of cytokines (six growth factors cocktail or granulocyte-macrophage colony-stimulating factor (CSF) or granulocyte-CSF) in combination with dasatinib. In the presence of cytokines, short-term intense Bcr-Abl kinase inhibition (>or=90% p-Crkl inhibition) with 100 nM dasatinib did not reduce CD34(+) colony-forming cells (CFCs). In contrast, without cytokines, short-term exposure to dasatinib reduced CML-CD34(+) CFCs by 70-80%. When cytokines were added immediately after short-term exposure to dasatinib, CML-CD34(+) cells remained viable, suggesting that oncogene dependence of these cells can be overcome by concomitant or subsequent exposure to cytokines. Additional inhibition of Janus tyrosine kinase (Jak) activity re-established the sensitivity of CML progenitors to intense Bcr-Abl kinase inhibition despite the presence of cytokines. These findings support the contention that therapeutic strategies combining intense Bcr-Abl kinase inhibition and blockade of cytokine signaling pathways can be effective for eradication of CML progenitors.
PMID: 20130598 [PubMed - indexed for MEDLINE]
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Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia.
Leukemia. 2010 Apr;24(4):699-705
Authors: Lancet JE, Gojo I, Burton M, Quinn M, Tighe SM, Kersey K, Zhong Z, Albitar MX, Bhalla K, Hannah AL, Baer MR
Heat shock protein 90 (Hsp90) is a molecular chaperone with many oncogenic client proteins. The small-molecule Hsp90 inhibitor alvespimycin, a geldanamycin derivative, is being developed for various malignancies. This phase 1 study examined the maximum-tolerated dose (MTD), safety and pharmacokinetic/pharmacodynamic profiles of alvespimycin in patients with advanced acute myeloid leukemia (AML). Patients with advanced AML received escalating doses of intravenous alvespimycin (8-32 mg/m(2)), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m(2) twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m(2) (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C(max) and area under the curve (AUC) from 8 to 32 mg/m(2) and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twice-weekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m(2).
PMID: 20111068 [PubMed - indexed for MEDLINE]
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BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells.
Blood. 2010 Apr 22;115(16):3185-95
Authors: Schemionek M, Elling C, Steidl U, Bäumer N, Hamilton A, Spieker T, Göthert JR, Stehling M, Wagers A, Huettner CS, Tenen DG, Tickenbrock L, Berdel WE, Serve H, Holyoake TL, Müller-Tidow C, Koschmieder S
In a previously developed inducible transgenic mouse model of chronic myeloid leukemia, we now demonstrate that the disease is transplantable using BCR-ABL(+) Lin(-)Sca-1(+)c-kit(+) (LSK) cells. Interestingly, the phenotype is more severe when unfractionated bone marrow cells are transplanted, yet neither progenitor cells (Lin(-)Sca-1(-)c-kit(+)), nor mature granulocytes (CD11b(+)Gr-1(+)), nor potential stem cell niche cells (CD45(-)Ter119(-)) are able to transmit the disease or alter the phenotype. The phenotype is largely independent of BCR-ABL priming before transplantation. However, prolonged BCR-ABL expression abrogates the potential of LSK cells to induce full-blown disease in secondary recipients and increases the fraction of multipotent progenitor cells at the expense of long-term hematopoietic stem cells (LT-HSCs) in the bone marrow. BCR-ABL alters the expression of genes involved in proliferation, survival, and hematopoietic development, probably contributing to the reduced LT-HSC frequency within BCR-ABL(+) LSK cells. Reversion of BCR-ABL, or treatment with imatinib, eradicates mature cells, whereas leukemic stem cells persist, giving rise to relapsed chronic myeloid leukemia on reinduction of BCR-ABL, or imatinib withdrawal. Our results suggest that BCR-ABL induces differentiation of LT-HSCs and decreases their self-renewal capacity.
PMID: 20053753 [PubMed - indexed for MEDLINE]
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Transferrin receptor-targeted liposomes encapsulating anti-BCR-ABL siRNA or asODN for chronic myeloid leukemia treatment.
Bioconjug Chem. 2010 Jan;21(1):157-68
Authors: Mendonça LS, Firmino F, Moreira JN, Pedroso de Lima MC, Simões S
The present work aimed at the development and application of transferrin receptor (TrfR)-targeted sterically stabilized liposomes encapsulating anti-BCR-ABL siRNA or asODN. Transferrin was coupled to the surface of liposomes encapsulating siRNA or asODN through the postinsertion method. Cell association and internalization were assessed by flow cytometry and confocal microscopy, respectively. BCR-ABL mRNA and Bcr-Abl protein levels were evaluated by qRT-PCR and Western blot, respectively. Cell viability was assessed using the resazurin reduction method. The amount of coupled transferrin and the size and stability over time of the liposomes were very satisfactory and reproducible. The siRNA encapsulation yield was dependent on the concentration of the encapsulation buffer used (20 or 300 mM), as opposed to asODN encapsulation yield which was high for both concentrations tested. Cell association and internalization studies were performed in leukemia cell lines treated with liposomes coupled to Trf (Trf-liposomes) or albumin (BSA-liposomes) or with nontargeted liposomes (NT-liposomes) encapsulating fluorescently labeled siRNA (Cy3-siRNA). These experiments clearly indicated that BSA- and NT-liposomes have no ability to promote the delivery of the encapsulated nucleic acids and that the Trf-liposomes deliver the nucleic acids by a Trf receptor-dependent mechanism. The Trf-liposomes encapsulating siRNA or asODN promote sequence-specific down-regulation of the BCR-ABL mRNA, although a certain extent of nonspecific sequence effects at the protein and cell viability level were observed. Overall, our results indicate that Trf-liposomes encapsulating gene silencing tools allow combining molecular and cellular targeting, which is a valuable approach for cancer treatment.
PMID: 20000596 [PubMed - indexed for MEDLINE]
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Posted by rob on May 20, 2010 under Uncategorized |
Conclusion:
To our knowledge, this is the first report to show that pristimerin is effective in vitro and in vivo against CML cells, including those with the T315I mutation. The mechanisms may involve inhibition of NF-kappaB and Bcr-Abl. We concluded that pristimerin could be a lead compound for further drug development to overcome imatinib resistance in CML patients. (Source: BioMed Central)
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New research discovers a combination of drugs that may prove to be a more effective treatment for a lethal form of leukemia. The study, published by Cell Press in the May issue of the journal Cancer Cell, reports that the new therapeutic strategy effectively targets notoriously intractable leukemia stem cells that often escape standard treatment and are a main factor in disease relapse. Chronic myelogenous leukemia (CML) is a deadly form of leukemia that is associated with chromosome rearrangements that result in the expression of the BCR-ABL oncoprotein… (Source: Health News from Medical News Today)
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Bin Zhang, Adam C. Strauss, Su Chu, Min Li, Yinwei Ho, Keh-Dong Shiang, David S. Snyder, Claudia S. Huettner, Leonard Shultz, Tessa Holyoake, Ravi Bhatia. Imatinib mesylate (IM) induces remission in chronic myelogenous leukemia (CML) patients but does not eliminate leukemia stem cells (LSCs), which remain a potential source of relapse. Here we inves…. (Source: Cancer Cell)
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CONCLUSIONS: CD4+ DLI results in rapid expansion of preexisting marrow-resident leukemia-specific donor CD8+ T cells, followed by a cascade of antigen-specific immune responses detectable in blood. Our single-antigen analysis thus shows that durable posttransplant tumor immunity is directed in part against nonpolymorphic overexpressed leukemia antigens that elicit coordinated cellular and humoral immunity.
PMID: 20460482 [PubMed - in process] (Source: Clinical Cancer Research)
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