Posted by rob on January 22, 2010 under Uncategorized | 
Modulation of Akt and ERK1/2 pathways by resveratrol in chronic myelogenous leukemia (CML) cells results in the downregulation of Hsp70.
PLoS One. 2010;5(1):e8719
Authors: Banerjee Mustafi S, Chakraborty PK, Raha S
BACKGROUND: Resveratrol is known to downregulate the high endogenous level of Heat shock protein 70 (Hsp70) in Chronic Myelogenous Leukemia (CML) K562 cells and induce apoptosis. Since Heat Shock Factor 1 (HSF1) controls transcription of Hsp70, we wanted to probe the signaling pathways responsible for transcriptional activation of HSF1. METHODOLOGY/PRINCIPAL FINDINGS: Cells exposed to 40microM Resveratrol rapidly abolished serine473 phosphorylation of Akt and significantly reduced its kinase activity. Inactivation of Akt pathway by Resveratrol subsequently blocked serine9 phosphorylation of Gsk3beta. Active non-phosphorylated Gsk3beta rendered HSF1 transcriptionally inactive and reduced Hsp70 production. Blocking PI3K/Akt activity also demonstrated similar effects on Hsp70 comparable to Resveratrol. Inactivation of Gsk3beta activity by inhibitors SB261763 or LiCl upregulated Hsp70. Resveratrol significantly modulated ERK1/2 activity as evident from hyper phosphorylation at T302/Y304 residues and simultaneous upregulation in kinase activity. Blocking ERK1/2 activation resulted in induction of Hsp70. Therefore, increase in ERK1/2 activity by Resveratrol provided another negative influence on Hsp70 levels through negative regulation of HSF1 activity. 17-allylamino-17-demethoxygeldanamycin (17AAG), a drug that inhibits Hsp90 chaperone and degrades its client protein Akt concomitantly elevated Hsp70 levels by promoting nuclear translocation of HSF1 from the cytosol. This effect is predominantly due to inhibition of both Akt and ERK1/2 activation by 17AAG. Simultaneously treating K562 with Resveratrol and 17AAG maintained phosho-ERK1/2 levels close to untreated controls demonstrating their opposite effects on ERK1/2 pathway. Resveratrol was found not to interfere with Bcr-Abl activation in K562 cells. CONCLUSION/SIGNIFICANCE: Thus our study comprehensively illustrates that Resveratrol acts downstream of Bcr-Abl and inhibits Akt activity but stimulates ERK1/2 activity. This brings down the transcriptional activity of HSF1 and Hsp70 production in K562 cells. Additionally, Resveratrol can be used in combination with chemotherapeutic agents such as 17AAG, an Hsp90 inhibitor reported to induce Hsp70 and hence compromise its chemotherapeutic potential.
PMID: 20090934 [PubMed - in process]
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A Review of Kinases Implicated in Pancreatic Cancer.
Pancreatology. 2010 Jan 15;9(6):738-754
Authors: Giroux V, Dagorn JC, Iovanna JL
The current 5-year survival rate of pancreatic cancer is about 3% and the median survival less than 6 months because the chemotherapy and radiation therapy presently available provide only marginal benefit. Clearly, pancreatic cancer requires new therapeutic concepts. Recently, the kinase inhibitors imatinib and gefitinib, developed to treat chronic myelogenous leukaemia and breast cancer, respectively, gave very good results. Kinases are deregulated in many diseases, including cancer. Given that phosphorylation controls cell survival signalling, strategies targeting kinases should obviously improve cancer treatment. The purpose of this review is to summarize the present knowledge on kinases potentially usable as therapeutic targets in the treatment of pancreatic cancer. All clinical trials using available kinase inhibitors in monotherapy or in combination with chemotherapeutic drugs failed to improve survival of patients with pancreatic cancer. To detect kinases relevant to this disease, we undertook a systematic screening of the human kinome to define a ’survival kinase’ catalogue for pancreatic cells. We selected 56 kinases that are potential therapeutic targets in pancreatic cancer. Preclinical studies using combined inhibition of PAK7, MAP3K7 and CK2 survival kinases in vitro and in vivo showed a cumulative effect on apoptosis induction. We also observed that these three kinases are rather specific of pancreatic cancer cells. In conclusion, if kinase inhibitors presently available are unfortunately not efficient for treating pancreatic cancer, recent data suggest that inhibitors of other kinases, involved more specifically in pancreatic cancer development, might, in the future, become interesting therapeutic targets. and IAP.
PMID: 20090395 [PubMed - as supplied by publisher]
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Herpetic geometric glossitis: Acyclovir resistant case in a patient with acute myelogenous leukemia.
Indian J Pathol Microbiol. 2010 Jan-Mar;53(1):133-4
Authors: Pereira CM, Souza CA, Correa ME
Herpes simplex virus (HSV) infections in an immunocompromised host may be atypical in location and morphology. Lesions are more extensive and aggressive, slow healing or nonhealing and extremely painful. Intraoral lesions are ulcerative and may involve any intraoral, oropharyngeal, or esophageal site. Herpetic geometric glossitis is a recently described form of lingual HSV infection in an immunocompromised patient. It was described as ulcer on the dorsum of the tongue sensitive for acyclovir therapy. A patient is presented with acute myelogenous leukemia that developed herpetic geometric glossitis which was acyclovir resistant.
PMID: 20090244 [PubMed - in process]
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Is there any relationship between imatinib mesylate medication and hypothalamic-pituitary-adrenal axis dysfunction?
Int J Clin Pract. 2010 Jan;64(1):45-50
Authors: Bilgir O, Kebapcilar L, Bilgir F, Sarì I, Oner P, Karaca B, Alacacioglu I
SUMMARY BACKGROUND: Imatinib mesylate [tyrosine kinase (TK) inhibitor] is a novel medication in the treatment of chronic myelogenous leukaemia (CML). TK is also essential in hypothalamo-pituitary-adrenal (HPA) axis. PURPOSE: The aim of this study was to evaluate HPA axis in patients treated with imatinib. Twenty-five patients were included in this study. METHODS: Glucagon stimulation test (GST) and low-dose (1 microg) adrenocorticotropin test (LDSST) were used to assess the HPA gland axis. Results: Seventeen (68%) subjects had impaired peak response when a cortisol cut-off value is accepted as 500 nmol/L. Twelve (48%) out of 17 subjects also failed to show a response to LDSST. Therefore, 12 patients (48%) were defined as HPA deficient. Only two of these 25 patients had morning serum cortisol < 200 nmol/l (7.22 microg/dl), and failed the GST and/or LDSST, indicating that the majority had partial glucocorticoid deficiency. If the cut-off presume for LDSST is from 500 to 600 nmol/l, 16 patients (64%) would have failed both the GST and LDSST. Conclusion: Our results indicate an increased prevalence of subclinical glucocorticoid deficiency in patients receiving imatinib mesylate for CML. Therefore under stressed conditions, such as intercurrent illness state, overt and untreated partial glucocorticoid deficiency in CML patients become life threatening.
PMID: 20089016 [PubMed - in process]
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c-Abl and Src-family kinases cross-talk in regulation of myeloid cell migration.
FEBS Lett. 2010 Jan 4;584(1):15-21
Authors: Baruzzi A, Iacobucci I, Soverini S, Lowell CA, Martinelli G, Berton G
Cytoskeleton dynamics are regulated by Src-family tyrosine kinases (SFKs) and c-Abl. We found that the SFK members Hck and c-Fgr regulate tyrosine phosphorylation of c-Abl and c-Abl associates with beta1 integrin-bound Hck or c-Fgr in murine macrophages. Studies with selective inhibitors and cells from SFK-deficient mice showed that c-Abl and SFK regulate migration and activation of the small GTPases Cdc42 and Rac in macrophages. Additionally, human neutrophil chemotactic activity was reduced by c-Abl inhibitors, and neutrophils from chronic myeloid leukaemia patients displayed an increased chemotactic ability. Hence, Src-family kinase and c-Abl cross-talk in the regulation of myeloid cell migration.
PMID: 19903482 [PubMed - indexed for MEDLINE]
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BK nephropathy in pediatric hematopoietic stem cell transplant recipients.
Pediatr Transplant. 2009 Nov;13(7):913-8
Authors: Verghese PS, Finn LS, Englund JA, Sanders JE, Hingorani SR
BK nephropathy is a known cause of renal insufficiency in kidney transplant recipients. Activation of the polyoma virus may also occur in the native kidneys of non-renal allograft recipients. BK nephropathy has only been reported in a few patients after HCT, most being adult patients, and the single reported pediatric case had evidence of hemorrhagic cystitis. The response to antiviral therapy also seems to differ widely. Here, we describe two cases of BK nephropathy in the native kidneys of HCT recipients exposed to high levels of immunosuppression because of GVHD. Neither of our patients had any evidence of hemorrhagic cystitis. We present definitive renal pathology and detailed chronological evidence of the rising serum creatinine with simultaneous serum and urine BK PCR titers. In one of our cases, antiviral therapy did not seem beneficial as documented by continued renal dysfunction and elevated serum/urine BK PCR titers. Based on our report, intense immunosuppression in pediatric HCT recipients seems to be involved in the activation of BK virus and BK nephropathy should be suspected even in the absence of hematuria in HCT recipients with unexplained renal dysfunction.
PMID: 19067914 [PubMed - indexed for MEDLINE]
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Influences of interferon-alpha on expression of Th cytokines and CCR7 in dendritic cells from patients with chronic myeloid leukemia in vitro.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008 Apr;16(2):401-5
Authors: Zhao WL, Chai YH, He HL, Wei XC, Wang T, Xing PN, Li MS
This study was aimed to investigate the influences of interferonalpha (IFN-alpha) on expressions of CCR7, interleukin10 (IL-10) and IL-12p70 in dendritic cells (DCs) from patients with chronic myeloid leukemia (CML). In addition to stem cell factor (SCF), granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha) and IL-4, IFN-alpha was added to the serum-free medium of DCs. After culture for 10-14 days, phenotypes and function of CML-DCs were evaluated respectively by flow cytometry and methyl thiazolyl tetrazolium (MTT) assay. Chromosome of DCs was analyzed by displaying G banding assay. The concentrations of IL-10 and IL-12P70 in supernatants were evaluated by enzyme-linked immunosorbent assay (ELISA). The results showed that the expressions of CD40, CD83, CD86 and CCR7 and the OD value in allogeneic mixed-lymphocyte reaction (MLR) in group with IFN-alpha (300 U/ml) were twice as high as those in group without IFN-alpha. The percentage of Ph1 positive cells and concentrations of IL-10 and IL-12 P70 were reduced in group with IFN-alpha. It is concluded that the defective phenotypes and functions of CML-DCs can be recruited partly by IFN-alpha. The mechanism may lie in the facts that expression of CCR7 and co-stimulatory molecules is promoted and the inhibitory effect of IL-10 on CML-DCs is relieved partly through the regulation of IFN-alpha.
PMID: 18426674 [PubMed - indexed for MEDLINE]
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[Research advance on molecular genetics of CML blast crisis]
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2008 Feb;16(1):217-21
Authors: Zhu HQ, Zhang S, Liu XL
Philadelphia (Ph) chromosome at (9; 22) reciprocal chromosomal translocation producing BCR-ABL fusion gene, emerges in almost all patients with chronic myeloid leukemia (CML). The protein product of BCR-ABL is a constitutively active tyrosine kinase that drives the abnormal proliferation of CML cells. Blast crisis (BC) is the terminal phase of CML, which is often associated with additional chromosomal and molecular secondary changes. Although the mechanisms responsible for transition of CML chronic phase (CP) into BC remain poorly understood, ample evidence suggests that it depends on synergy of BCR/ABL with other genes dysregulated during disease progression, and signaling pathways are abnormally activated by BCR/ABL. With the application of imatinib, a ABL-specific tyrosine kinase inhibitor, its remarkable therapeutic effects suggest that blast crisis transition will be postponed in most patients with CML. Rate of cumulative best response in CML-CP patients from the IRIS trial after 5 years are 98% for complete hematologic response, 92% for major cytogenetic response and 87% for complete cytogenetic response. However, a minority of CML-CP patients and most patients in progression either fail or respond suboptimally to imatinib. There are many distinct patterns of resistance, and ABL kinase mutations is a common finding associated with clinical resistance. Dasatinib and nilotinib can restore hematologic and cytogenetic remission in the majority of patients with primary failure or acquired resistance in chronic phase. This review illustrates the molecular mechanisms underlying transition to CML-BC, also addresses oneself to how and why imatinib resistance occurs.
PMID: 18315935 [PubMed - indexed for MEDLINE]
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