CiteULike: carmenv's library [24 articles]

The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl–Crk pathway

Nicole Noren — 2006-08-02T02:26:56-00:00

Nature Cell Biology, Vol. 8, No. 8. (23 July 2006), pp. 815-825.

Eph-ephrin signalling in adult tissues and cancer.

A Merlos-Suárez — 2008-05-15T16:56:36-00:00

Current opinion in cell biology, Vol. 20, No. 2. (April 2008), pp. 194-200.

Eph receptor tyrosine kinases and their ligands, the ephrins, play key roles in the regulation of migration and cell adhesion during development, thereby influencing cell fate, morphogenesis and organogenesis. Recent findings suggest that Eph signalling also controls the architecture and physiology of different tissues in the adult body under normal and pathological conditions such as cancer. A prime example is the intestinal epithelium where EphB-ephrinB interactions regulate both cell positioning and tumor progression. Here, we will review recent advances on the role of Eph-ephrin signalling in the intestine and other organs.

In human leukemia cells ephrin-B-induced invasive activity is supported by Lck and is associated with reassembling of lipid raft signaling complexes.

G Jiang — 2008-05-15T16:55:19-00:00

Molecular cancer research : MCR, Vol. 6, No. 2. (February 2008), pp. 291-305.

Proteins of the ephrin-B group operate in nonlymphoid cells through the control of their migration and attachment, and are crucial for the development of the vascular, lymphatic, and nervous systems. Ephrin-B activity is deregulated in various nonlymphoid malignancies; however, their precise role in cancer has only started to be addressed. We show here that ephrin-B1, a member of the ephrin-B group, is expressed in pediatric T-cell leukemias, including leukemia cell line Jurkat. Treatment of Jurkat cells with ephrin-B-stimulating EphB3 enhances ephrin-B1 phosphorylation and induces its relocalization into lipid rafts. These events are mediated by the T lineage-specific kinase, Lck, as ephrin-B1 phosphorylation and lipid raft association are blocked in the Lck-deficient clone of Jurkat, JCAM1.6. Ephrin-B1 also induces colocalization of the CrkL and Rac1 cytoskeleton regulators and initiates in leukemic cells a strong repulsive response. The absence of Lck blocks ephrin-B1-induced signaling and repulsion, confirming the essential role for Lck in ephrin-B1-mediated responses. This shows a new role for ephrin-B1 in the regulation of leukemic cells through the Lck-dependent Rac1 colocalization with its signaling partner, CrkL, in lipid rafts. In agreement with its repulsive action, ephrin-B1 seems to support metastatic properties of leukemic cells, as suppression of ephrin-B1 signaling inhibits their invasiveness. Because ephrin-B1-activating EphB proteins are ubiquitously expressed, our findings suggest that ephrin-B1 is likely to play an important role in the regulation of malignant T lymphocytes through the control of lipid-raft-associated signaling, adhesion, and invasive activity, and therefore may represent a novel target for cancer treatment.

Monoclonal antibodies target intracellular PRL phosphatases to inhibit cancer metastases in mice.

Ke Guo — 2008-05-15T00:00:02-00:00

Cancer biology & therapy, Vol. 7, No. 5. (20 February 2008)

PRL-1 (phosphatase of regenerating liver-1), PRL-2, and PRL-3 are protein tyrosine phosphatases with a C-terminal prenylation motif that are localized to the inner leaflet of the plasma membrane and early endosomes. A variety of metastatic PRL-overexpressing cancers have been reported. Therefore, the three PRL-phosphatases represent an intriguing group of proteins being validated as biomarkers and therapeutic targets in cancer. Targeting intracellular PRLs to prevent cancer metastasis by exogenous reagents is a challenging task. In an attempt to destroy PRL-overexpressing cancer cells with their respective PRL-antibodies, we generated an animal model that allows rapid formation of aggressive metastatic tumors caused by inoculation of PRL-1- or PRL-3-expressing cells. Surprisingly, mice treated with PRL-1 or PRL-3 mAbs show inhibition of tumor formation by approximately 90% compared to untreated mice. Here we provide the first examples that PRL-1 and PRL-3 mAbs are able to target their respective phosphatases specifically and efficiently despite their intracellular localization to block cancer metastasis in experimental animals. Furthermore, we also demonstrate that PRL-1 mAb specifically blocks the formation of metastatic tumors formed by PRL-1- (but not PRL-3-) expressing cells; while PRL-3 mAb specifically blocks tumor formation of PRL-3- (but not PRL-1-) expressing cells. More importantly, we show that metastatic tumor formation by A2780 human ovarian cancer cells that express endogenous PRL-3 is dramatically blocked by PRL-3 antibodies. In contrast, the PRL-3 antibody treatment has no effect on tumor formation of CT26 mouse colon cancer cells which do not naturally express PRL-3 protein. Our data provide hope for the treatment of PRL-expressing cancers and will prompt a reevaluation of a wide spectrum of intracellular oncoproteins as possible targets with mAbs for anticancer therapy.

Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer.

Robyn L Prueitt — 2008-05-14T23:34:41-00:00

The Prostate (5 May 2008)

BACKGROUND: Perineural invasion (PNI) is the dominant pathway for local invasion in prostate cancer. To date, only few studies have investigated the molecular differences between prostate tumors with PNI and those without it. METHODS: To evaluate the involvement of both microRNAs and protein-coding genes in PNI, we determined their genome-wide expression with a custom microRNA microarray and Affymetrix GeneChips in 50 prostate adenocarcinomas with PNI and 7 without it. In situ hybridization (ISH) and immunohistochemistry was used to validate candidate genes. RESULTS: Unsupervised classification of the 57 adenocarcinomas revealed two clusters of tumors with distinct global microRNA expression. One cluster contained all non-PNI tumors and a subgroup of PNI tumors. Significance analysis of microarray data yielded a list of microRNAs associated with PNI. At a false discovery rate (FDR) <10%, 19 microRNAs were higher expressed in PNI tumors than in non-PNI tumors. The most differently expressed microRNA was miR-224. ISH showed that this microRNA is expressed by perineural cancer cells. The analysis of protein-coding genes identified 34 transcripts that were differently expressed by PNI status (FDR < 10%). These transcripts were down-regulated in PNI tumors. Many of those encoded metallothioneins and proteins with mitochondrial localization and involvement in cell metabolism. Consistent with the microarray data, perineural cancer cells tended to have lower metallothionein expression by immunohistochemistry than nonperineural cancer cells. CONCLUSIONS: Although preliminary, our findings suggest that alterations in microRNA expression, mitochondrial function, and cell metabolism occur at the transition from a noninvasive prostate tumor to a tumor with PNI. Prostate Published 2008 Wiley-Liss, Inc.

Cancerous miRNAs and their regulation.

Xu-Bao Shi — 2008-05-14T23:32:18-00:00

Cell cycle (Georgetown, Tex.), Vol. 7, No. 11. (19 March 2008)

Although they account for only a very minor fraction of the expressed genome, microRNAs (miRNAs) are pivotal regulators of development and cellular homeostasis through their control of diverse cellular processes including proliferation, differentiation, apoptosis, survival, motility, and morphogenesis. Accordingly, several miRNAs have been functionally classified as proto-oncogenes or tumor suppressors and are aberrantly expressed in different cancer types. Deregulation (e.g., overexpression or loss of expression) of these so-called "cancerous" miRNAs can figure prominently in tumor initiation and progression by elaborating an inappropriate cellular program promoting uncontrolled proliferation, favoring survival, inhibiting differentiation, and/or promoting invasive behavior. These features would certainly promote tumor dissemination and persistence by favoring metastasis and therapy resistance. Cancerous miRNAs therefore represent attractive molecules for exploitation as biomarkers and therapeutic targets. In this review, we highlight recently characterized cancerous miRNAs and the mechanisms through which they contribute to the pathogenesis of human cancers. We also discuss the signal transduction pathways that regulate the expression of these miRNAs with particular attention to several essential transcription factors such as Myc, p53, and the androgen receptor.

Nelarabine- a new purine analog in the treatment of hematologic malignancies.

S Curbo — 2008-05-14T23:27:28-00:00

Reviews on recent clinical trials, Vol. 1, No. 3. (September 2006), pp. 185-192.

GW506U78 or nelarabine (Glaxo-SmithKline) is a nucleoside analog that is rapidly converted by cells of lymphoid lineage to its corresponding arabinosylguanine nucleotide triphosphate (araGTP). The triphosphate form of araG acts as a substrate for DNA polymerases and araG gets incorporated into the DNA, resulting in inhibition of DNA synthesis and subsequent cytotoxicity. It has been shown that nelarabine has activity as a single agent in patients with T-cell malignancies that have relapsed or are refractory to other therapy. The ongoing research on nelarabine has earned fast-track status from the U.S. Food and Drug Administration (FDA) for treatment of patients with T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma who have not responded to or whose disease has progressed during treatment with at least two standard regimens. It is likely that nelarabine will be a useful drug in the treatment of leukemic diseases in the future and therefore nelarabine is an interesting drug to study further. Here we present an overview of what is known about the mechanism of action of nelarabine and its status in clinical trials.

Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability.

N Widmer — 2008-05-14T23:25:23-00:00

British journal of cancer, Vol. 98, No. 10. (20 May 2008), pp. 1633-1640.

Imatinib has revolutionised the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST). Using a nonlinear mixed effects population model, individual estimates of pharmacokinetic parameters were derived and used to estimate imatinib exposure (area under the curve, AUC) in 58 patients. Plasma-free concentration was deduced from a model incorporating plasma levels of alpha(1)-acid glycoprotein. Associations between AUC (or clearance) and response or incidence of side effects were explored by logistic regression analysis. Influence of KIT genotype was also assessed in GIST patients. Both total (in GIST) and free drug exposure (in CML and GIST) correlated with the occurrence and number of side effects (e.g. odds ratio 2.7+/-0.6 for a two-fold free AUC increase in GIST; P<0.001). Higher free AUC also predicted a higher probability of therapeutic response in GIST (odds ratio 2.6+/-1.1; P=0.026) when taking into account tumour KIT genotype (strongest association in patients harbouring exon 9 mutation or wild-type KIT, known to decrease tumour sensitivity towards imatinib). In CML, no straightforward concentration-response relationships were obtained. Our findings represent additional arguments to further evaluate the usefulness of individualising imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients.British Journal of Cancer (2008) 98, 1633-1640. doi:10.1038/sj.bjc.6604355 www.bjcancer.com Published online 6 May 2008.

Vimentin affects the mobility and invasiveness of prostate cancer cells.

Yan Zhao — 2008-05-12T22:19:57-00:00

Cell biochemistry and function (8 May 2008)

A significant proportion of prostate cancer patients treated with curative intent go on to develop advanced disease. At a fundamental biological level, very little is known about what makes the disease aggressive and metastatic. Observational pathology reports and experimental data suggest that epithelial-mesenchymal transition is involved in prostate cancer invasiveness. Here, we investigated vimentin expression of prostate cancer cells, and explored the potential mechanism of vimentin promoting prostate cancer cells invasion. Vimentin expression was not detected in well differentiated tumors or in moderately differentiated tumors, but the majority of poorly differentiated cancers (5/11 with negative bone scan, 11/14 bone with positive scan) and bone metastases (8/8) had high vimentin expression in tumor cells. Downregulation of vimentin expression in PC-3 cells by transfection with antisense-vimentin led to a significant decrease in tumor cells motility and invasive activity. Furthermore, the expression of E-cadherin was inversely associated with expression of vimentin. Our results suggest that vimentin affects prostate cancer cells motility and invasiveness. Copyright (c) 2008 John Wiley & Sons, Ltd.

Protein tyrosine phosphatases: functional inferences from mouse models and human diseases

Hendriks — 2008-02-11T00:18:06-00:00

FEBS Journal, Vol. 275, No. 5. (March 2008), pp. 816-830.

Important role of the LKB1-AMPK pathway in suppressing tumourigenesis in PTEN deficient mice.

Xu Huang — 2008-05-09T20:36:26-00:00

The Biochemical journal (3 April 2008)

The LKB1 tumour suppressor phosphorylates and activates AMPK when cellular energy levels are low, thereby suppressing growth through multiple pathways, including inhibiting the mTORC1 kinase that is activated in the majority of human cancers. Blood glucose lowering type-2 diabetes drugs also induce LKB1 to activate AMPK, indicating that these compounds could be used to suppress growth of tumour cells. In this study we investigated the importance of the LKB1-AMPK pathway in regulating tumourigenesis in mice resulting from deficiency of the PTEN tumour suppressor, which drives cell growth through over-activation of the Akt and mTOR kinases. We demonstrate that inhibition of AMPK resulting from a hypomorphic mutation that decreases LKB1 expression does not lead to tumourigenesis on its own, but markedly accelerated tumour development in PTEN+/- mice. In contrast, activating the AMPK pathway by administration of PTEN+/- mice metformin, phenformin or A-769662, significantly delayed tumour onset. We demonstrate that LKB1 is required for activators of AMPK to inhibit mTORC1 signalling as well as cell growth in PTEN deficient cells. Our findings highlight in an animal model relevant to understanding human cancer, the vital role that the LKB1-AMPK pathway plays in suppressing tumourigenesis resulting from loss of PTEN tumour suppressor. They also suggest that pharmacological inhibition of LKB1 and/or AMPK would be undesirable, at least for the treatment of cancers in which the mTORC1-pathway is activated. Most importantly our data demonstrate the potential of AMPK activators such as clinically approved metformin as anti-cancer agents, which will suppress tumour development by triggering a physiological signalling pathway that potently inhibits cell growth.

UVB irradiation regulates Cox-2 mRNA stability through AMPK and HuR in human keratinocytes.

Jack Zhang — 2008-05-09T20:34:34-00:00

Molecular carcinogenesis (30 April 2008)

Considerable evidence has demonstrated that UVB irradiation is a strong carcinogen for nonmelanoma skin cancer. Up-regulation of cyclooxygenase -2 (Cox-2) has been shown to be a crucial event in human keratinocytes in their responses to UVB irradiation. To further understand the molecular mechanisms governing Cox-2 regulation, we found that UVB irradiation significantly increased Cox-2 mRNA stability by inducing cytoplasmic localization and protein abundance of human antigen R (HuR). We also found that AMP-activated kinase (AMPK) mediates these events and that UVB reduces AMPK activity by down-regulating LKB1 kinase. Finally, we propose a novel model in which UVB regulates Cox-2 mRNA stability through the LKB1/AMPK pathway. (c) 2008 Wiley-Liss, Inc.

Re-examining the role of cytochrome c in cell death

Eric Solary — 2008-03-27T14:38:30-00:00

Nat Genet, Vol. 40, No. 4. (April 2008), pp. 379-380.

Senescence, apoptosis or autophagy? When a damaged cell must decide its path--a mini-review.

JM Vicencio — 2008-05-09T20:17:30-00:00

Gerontology, Vol. 54, No. 2. (2008), pp. 92-99.

Many features of aging result from the incapacity of cells to adapt to stress conditions. When damage accumulates irreversibly, mitotic cells from renewable tissues rely on either of two mechanisms to avoid replication. They can permanently arrest the cell cycle (cellular senescence) or trigger cell death programs. Apoptosis (self-killing) is the best-described form of programmed cell death, but autophagy (self-eating), which is a lysosomal degradation pathway essential for homeostasis, reportedly contributes to cell death as well. Unlike mitotic cells, postmitotic cells like neurons or cardiomyocytes cannot become senescent since they are already terminally differentiated. The fate of these cells entirely depends on their ability to cope with stress. Autophagy then operates as a major homeostatic mechanism to eliminate damaged organelles, long-lived or aberrant proteins and superfluous portions of the cytoplasm. In this mini-review, we briefly summarize the molecular networks that allow damaged cells either to adapt to stress or to engage in programmed-cell-death pathways.

Regulation of autophagy by cytoplasmic p53.

Ezgi Tasdemir — 2008-05-09T20:16:01-00:00

Nature cell biology (4 May 2008)

Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.

Src kinase regulation by phosphorylation and dephosphorylation.

R Roskoski — 2006-02-28T10:23:59-00:00

Biochem Biophys Res Commun, Vol. 331, No. 1. (27 May 2005), pp. 1-14.

Src and Src-family protein-tyrosine kinases are regulatory proteins that play key roles in cell differentiation, motility, proliferation, and survival. The initially described phosphorylation sites of Src include an activating phosphotyrosine 416 that results from autophosphorylation, and an inhibiting phosphotyrosine 527 that results from phosphorylation by C-terminal Src kinase (Csk) and Csk homologous kinase. Dephosphorylation of phosphotyrosine 527 increases Src kinase activity. Candidate phosphotyrosine 527 phosphatases include cytoplasmic PTP1B, Shp1 and Shp2, and transmembrane enzymes include CD45, PTPalpha, PTPepsilon, and PTPlambda. Dephosphorylation of phosphotyrosine 416 decreases Src kinase activity. Thus far PTP-BL, the mouse homologue of human PTP-BAS, has been shown to dephosphorylate phosphotyrosine 416 in a regulatory fashion. The platelet-derived growth factor receptor protein-tyrosine kinase mediates the phosphorylation of Src Tyr138; this phosphorylation has no direct effect on Src kinase activity. The platelet-derived growth factor receptor and the ErbB2/HER2 growth factor receptor protein-tyrosine kinases mediate the phosphorylation of Src Tyr213 and activation of Src kinase activity. Src kinase is also a substrate for protein-serine/threonine kinases including protein kinase C (Ser12), protein kinase A (Ser17), and CDK1/cdc2 (Thr34, Thr46, and Ser72). Of the three protein-serine/threonine kinases, only phosphorylation by CDK1/cdc2 has been demonstrated to increase Src kinase activity. Although considerable information on the phosphoprotein phosphatases that catalyze the hydrolysis of Src phosphotyrosine 527 is at hand, the nature of the phosphatases that mediate the hydrolysis of phosphotyrosine 138 and 213, and phosphoserine and phosphothreonine residues has not been determined.

Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia.

R Xu — 2008-04-30T17:47:59-00:00

Blood, Vol. 106, No. 9. (1 November 2005), pp. 3142-3149.

Shp2 tyrosine phosphatase plays a critical role in hematopoiesis, and dominant active mutations have been detected in the human gene PTPN11, encoding Shp2, in child leukemia patients. We report here that although no such mutations were detected in 44 adult leukemia patients screened, Shp2 expression levels were significantly elevated in primary leukemia cells and leukemia cell lines, as compared with normal hematopoietic progenitor cells. The Shp2 protein amounts correlated well with the hyperproliferative capacity but were inversely associated with the differentiation degree of leukemia cells. Suppression of Shp2 expression induced apoptosis and inhibition of leukemic cell clonogenic growth. Notably, the majority of Shp2 was preferentially localized to the plasma membrane and was constitutively phosphorylated on tyrosine in leukemia cells, and also in normal hematopoietic cells following mitogenic stimulation. Based on these results, we propose that aberrantly increased expression of Shp2 may contribute, collaboratively with other factors, to leukemogenesis.

PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase.

RJ Chan — 2008-04-30T17:46:23-00:00

Blood, Vol. 109, No. 3. (1 February 2007), pp. 862-867.

Elucidation of the molecular mechanisms underlying carcinogenesis has benefited tremendously from the identification and characterization of oncogenes and tumor suppressor genes. One new advance in this field is the identification of PTPN11 as the first proto-oncogene that encodes a cytoplasmic tyrosine phosphatase with 2 Src-homology 2 (SH2) domains (Shp2). This tyrosine phosphatase was previously shown to play an essential role in normal hematopoiesis. More recently, somatic missense PTPN11 gain-of-function mutations have been detected in leukemias and rarely in solid tumors, and have been found to induce aberrant hyperactivation of the Ras-Erk pathway. This progress represents another milestone in the leukemia/cancer research field and provides a fresh view on the molecular mechanisms underlying cell transformation.

Activation of SHP2 protein-tyrosine phosphatase increases HoxA10-induced repression of the genes encoding gp91(PHOX) and p67(PHOX).

S Lindsey — 2008-04-30T17:44:10-00:00

The Journal of biological chemistry, Vol. 282, No. 4. (26 January 2007), pp. 2237-2249.

The CYBB and NCF2 genes encode the phagocyte oxidase proteins gp91(PHOX) and p67(PHOX), respectively. These genes are transcribed after the promyelocyte stage of differentiation, and transcription continues until cell death. In undifferentiated myeloid cells, homologous cis-elements in the CYBB and NCF2 genes are repressed by the homeodomain transcription factor HoxA10. During cytokine-induced myelopoiesis, tyrosine phosphorylation of HoxA10 decreases binding affinity for the CYBB and NCF2 cis-elements. This abrogates HoxA10-induced transcriptional repression as differentiation proceeds. Therefore, mechanisms involved in differentiation stage-specific HoxA10 tyrosine phosphorylation are of interest because HoxA10 phosphorylation modulates myeloid-specific gene transcription. In this study, we found that HoxA10 is a substrate for SHP2 protein-tyrosine phosphatase in undifferentiated myeloid cells. In contrast, HoxA10 is a substrate for a constitutively active mutant form of SHP2 in both undifferentiated and differentiating myeloid cells. Expression of such SHP2 mutants results in persistent HoxA10 repression of CYBB and NCF2 transcription during myelopoiesis. Both HoxA10 overexpression and activating SHP2 mutations have been described in human myeloid malignancies. Therefore, our results suggest that these mutations could cooperate, leading to decreased myeloid-specific gene transcription and functional differentiation block in myeloid cells with both defects.

Anti-cancer and anti-angiogenic effects of curcumin and tetrahydrocurcumin on implanted hepatocellular carcinoma in nude mice.

P Yoysungnoen — 2008-04-29T16:19:40-00:00

World journal of gastroenterology : WJG, Vol. 14, No. 13. (7 April 2008), pp. 2003-2009.

AIM: To determine the effect of tetrahydrocurcumin (THC) on tumor angiogenesis compared with curcumin (CUR) by using both in vitro and in vivo models of human hepatocellular carcinoma cell line (HepG2). METHODS: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used for testing the anti-proliferating activities of CUR and THC. In male BALB/c nude mice, 2 multiply 10(6) human HepG2 cells were inoculated onto a dorsal skin-fold chamber. One day after HepG2 inoculation, the experimental groups were fed oral daily with CUR or THC (300 mg/kg or 3000 mg/kg). On d 7, 14 and 21, the tumor microvasculature was observed using fluorescence videomicroscopy and capillary vascularity (CV) was measured. RESULTS: Pathological angiogenic features including microvascular dilatation, tortuosity, and hyper-permeability were observed. CUR and THC could attenuate these pathologic features. In HepG2-groups, the CV were significantly increased on d 7 (52.43%), 14 (69.17%), and 21 (74.08%), as compared to controls (33.04%, P < 0.001). Treatment with CUR and THC resulted in significant decrease in the CV (P < 0.005 and P < 0.001, respectively). In particular, the anti-angiogenic effects of CUR and THC were dose-dependent manner. However, the beneficial effect of THC treatment than CUR was observed, in particular, from the 21 d CV (44.96% and 52.86%, P < 0.05). CONCLUSION: THC expressed its anti-angiogenesis without any cytotoxic activities to HepG2 cells even at the highest doses. It is suggested that anti-angiogenic properties of CUR and THC represent a common potential mechanism for their anti-cancer actions.

Curcumin inhibits WEHI-3 leukemia cells in BALB/c mice in vivo.

CC Su — 2008-04-29T16:18:45-00:00

In vivo (Athens, Greece), Vol. 22, No. 1. (b 2008), pp. 63-68.

Curcumin (1, 7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5- dione), a natural polyphenol product of the plant Curcuma longa, exhibited potent inhibitory activities against proliferation, induced cell cycle arrest and exhibited the induction of apoptosis in several tumor cell lines. In our previous studies, we have shown that curcumin induced cell cycle arrest and apoptosis on human leukemia HL-60 and mouse leukemia WEHI-3 cells; there are no reports regarding whether or not it affects leukemia cells in vivo. In the present study, we investigated the effects of curcumin on WEHI-3 in BALB/c mice and the results indicated that curcumin reduces the percentage of Mac-3 marker, which is the precursor of macrophage. Curcumin induced significant effects on the population of B cells from murine leukemia in vivo. We also investigated the weights of spleen and liver from murine leukemia and the results showed that curcumin reduced the weight of the liver and spleen. From the pathological examinations, the effects of curcumin on the liver and spleen from mice after being injected with WEHI-3 cells were apparent. Both organs were enlarged. In conclusion, curcumin affect WEHI-3 cells in vivo.

Evaluation of a nanotechnology-based carrier for delivery of curcumin in prostate cancer cells.

RL Thangapazham — 2008-04-29T16:07:45-00:00

International journal of oncology, Vol. 32, No. 5. (May 2008), pp. 1119-1123.

We have initiated studies to enhance targeted delivery of an anticancer agent, curcumin, for prostate cancer treatment by incorporating this agent into the liposomes (nanodelivery vehicles primarily composed of phospholipids) coated with prostate membrane specific antigen specific antibodies. We prepared curcumin-loaded liposomes of various lipid compositions by sonication at an average size of 100-150 nm. Un-entrapped curcumin was removed by size exclusion chromatography. Data show that curcumin preferentially partitioned into liposomes prepared from dimyristoyl phosphatidyl choline (DMPC) and cholesterol among the various compositions tested. The anti-proliferative activity of liposomal curcumin was studied using two human prostate cancer cell lines (LNCaP and C4-2B) by a tetrazolium dye-based (MTT) assay. Treatment of cells with liposomal curcumin (5-10 microM) for 24-48 h at 37 degrees C resulted in at least 70-80% inhibition of cellular proliferation without affecting their viability. On the other hand, free curcumin exhibited similar inhibition only at 10-fold higher doses (>50 microM). We also observed that LNCaP cells were relatively more sensitive to liposomal curcumin mediated block of cellular proliferation than C4-2B cells. We are currently developing liposome formulations with targeting ability to further improve the efficacy of curcumin in vivo.

Curcuma drugs and curcumin regulate the expression and function of P-gp in Caco-2 cells in completely opposite ways.

Xiao-Long Hou — 2008-04-29T16:04:01-00:00

International journal of pharmaceutics (18 March 2008)

Curcumin is a phenolic compound isolated from rhizomes of C. longa, C. aromatica and other Curcumas except C. zedoaria. Recently, both curcumin and Curcumas have become prevalent as supplement. P-gp has been reported as an important determinant for drug absorption in small intestine. In this study, Caco-2 cell monolayers were treated with methanol extracts of Curcumas (0.1mg/ml) or curcumin (30muM) for 72h to investigate the relationship between the potential affects of Curcumas and curcumin on P-gp. [(3)H]-digoxin and rhodamine 123 were used to evaluate P-gp activity. All Curcumas significantly increased the activity of P-gp by up-regulating the expressions of P-gp protein and MDR1 mRNA levels. Interestingly, contrary to Curcumas, curcumin treatment inhibited the activity of P-gp with a decrease in P-gp protein and MDR1 mRNA expression levels. Curcumas might alter the pharmacokinetics of co-administrated drugs by up-regulating the function and expression levels of intestinal P-gp. However, curcumin has no relationship with the inductive effect of Curcumas since curcumin showed an opposite effects. Caution should be exercised when Curcumas or curcumin are to be consumed with drugs that are P-gp substrates because Curcumas and curcumin might regulate the function of P-gp in completely opposite ways.

Why have serine/threonine/tyrosine kinases been evolutionarily selected in eukaryotic signaling cascades?

Hyung-Seok Choi — 2008-04-29T15:56:10-00:00

Computational biology and chemistry (23 February 2008)

The signal transduction systems of eukaryotes are different from those of prokaryotes with respect to their structures and mechanisms. The main signal transduction system of prokaryotes called the two-component system (TCS) is a one-step phosphorelay system composed of a histidine kinase (HK) while the central signal transduction system of eukaryotes called the mitogen-activated protein kinase (MAPK) cascade system (MCS) is a multi-step phosphorelay system composed of serine/threonine/tyrosine kinases (STYKs). The two signal transduction systems are also different in their transphosphorylation mechanisms. HK in the TCS transfers its own phosphate group to the response regulator protein while STYKs in the MCS phosphorylate other proteins using ATP. We were intrigued by the different dynamics resulting from such differences and wondered why STYKs instead of HKs have been evolutionarily selected in eukaryotic signaling cascades. In this paper, we compared the dynamical characteristics of two mathematical models which reflect such differences between the TCS and the MCS, and found that STYKs are more appropriate for cascade structures in eukaryotic signal transduction than HK with respect to the duration and settling time of response signals.