Biomedical subjects

Sunmin Lee

Publications and source records attributed to Sunmin Lee.

At least 19 recordsLinked to original sources

PubMed2006

Assays for pharmacodynamic analysis of histone deacetylase inhibitors.

Histone deacetylase inhibitors (HDACIs) are a promising new class of targeted anticancer drugs. The pharmacodynamic (PD) assessment of whether a drug has hit its target is critically important to the successful development of any molecular targeted therapy. In the case of HDACIs there are many issues to be considered in PD development and implementation. Although originally it was thought that measurement of core histone hyperacetylation in peripheral blood mononuclear cells might suffice as a PD marker, as the field is evolving it is becoming evident that other measures may be essential, and are likely to be tumour context specific. This paper provides an overview of the assays that have been performed thus far in HDACI clinical trials, with an analysis of relative strengths and weaknesses, and a delineation of the complexity of HDACI PD analysis. Consideration is given to where new approaches are needed and potential approaches for future monotherapy and combination therapy trials are suggested.

Acetylation↗

PubMed2006

Curcumin is an inhibitor of p300 histone acetylatransferase.

Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant molecular targets for drug development. In this study, we demonstrate that the small molecule natural product curcumin, whose medicinal properties have long been recognized in India and Southeast Asia, is a selective HAT inhibitor. Furthermore the data indicate that alpha, beta unsaturated carbonyl groups in the curcumin side chain function as Michael reaction sites and that the Michael reaction acceptor functionality of curcumin is required for its HAT-inhibitory activity. In cells, curcumin promoted proteasome-dependent degradation of p300 and the closely related CBP protein without affecting the HATs PCAF or GCN5. In addition to inducing p300 degradation curcumin inhibited the acetyltransferase activity of purified p300 as assessed using either histone H3 or p53 as substrate. Radiolabeled curcumin formed a covalent association with p300, and tetrahydrocurcumin displayed no p300 inhibitory activity, consistent with a Michael reaction-dependent mechanism. Finally, curcumin was able to effectively block histone hyperacetylation in both PC3-M prostate cancer cells and peripheral blood lymphocytes induced by the histone deacetylase inhibitor MS-275. These data thus identify the medicinal natural product curcumin as a novel lead compound for development of possibly therapeutic, p300/CBP-specific HAT inhibitors.

Antineoplastic Agents↗

PubMed2005

The relation of education and income to cognitive function among professional women.

We investigated the relation of educational attainment and annual household income to cognitive function and cognitive decline in community-dwelling women aged 66 years or older. Subjects were 6,314 health professionals participating in the Women's Health Study, among whom information on education and income was self-reported. From 1998 to 2000, we administered five cognitive tests, measuring general cognition, episodic memory and verbal fluency, using a validated telephone interview. Second cognitive assessments were conducted approximately 2 years later; information was complete for 5,573 women at the time of analysis, with 94% follow-up. We used linear and logistic regression to calculate multivariate-adjusted mean differences as well as odds of cognitive impairment (defined as worst 10% of test distribution) and of substantial decline in performance (worst 10% of distribution), across various levels of education and income. After adjusting for numerous potential confounding factors, we found strong trends of increasing mean cognitive performance with increasing level of education (p trend<0.0005 on all cognitive measures). Odds of cognitive impairment also consistently decreased with increasing education. For income, we found significant trends of increasing mean cognitive performance with increasing income on the summary score and on episodic memory (p trends<0.0001). Results were generally similar for cognitive decline over 2 years, although slightly weaker. Thus, in these well-educated, professional women, educational attainment and income both predicted cognitive function and decline.

Aged↗

PubMed2005

Sequential 5-Aza 2'-deoxycytidine/depsipeptide FK228 treatment induces tissue factor pathway inhibitor 2 (TFPI-2) expression in cancer cells.

cDNA arrays were used to examine gene induction in CALU-6 and H460 lung cancer cells mediated by sequential 5-aza 2'-deoxycytidine (DAC)/depsipeptide FK228 (DP) exposure in order to identify translational end points for clinical trials evaluating these agents. In both cell lines, sequential DAC/DP treatment induced expression of tissue factor pathway inhibitor-2 (TFPI-2), an inhibitor of Factor VII: tissue factor signal transduction known to diminish the malignant phenotype of cancer cells. TFPI-2 expression was diminished or absent in 16 of 32 cell lines established from thoracic malignancies. Sequential DAC/DP treatment induced TFPI-2 in cancer cells deficient for TFPI-2 expression in the basal state. Promoter methylation coincided with loss of TFPI-2 expression in a number of cancer lines. TFPI-2 promoter methylation was observed in one of five pulmonary adenocarcinomas, and seven of seven esophageal adenocarcinomas, but not corresponding normal tissues. DP enhanced acetylation of TFPI-2-associated histones in CALU-6 cells. DP or PDBU, alone, induced TFPI-2 expression in cancer cells deficient for TFPI-2 expression in the absence of promoter methylation. In these cells, DP-mediated TFPI-2 induction was abrogated by calphostin. Induction of TFPI-2 by distinct, yet cooperative mechanisms involving chromatin remodeling and PKC signaling strengthens the preclinical rationale for sequential administration of DNA demethylating agents and HDAC inhibitors in cancer patients. Furthermore, induction of TFPI-2 may be a useful surrogate marker of treatment response in individuals receiving sequential DAC/DP infusions.

Azacitidine↗

PubMed2005

HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability.

Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.

Adult↗

PubMed2005

Chromosomal protein HMGN1 modulates the expression of N-cadherin.

HMGN1 is a nuclear protein that binds to nucleosomes and alters the accessibility of regulatory factors to their chromatin targets. To elucidate its biological function and identify specific HMGN1 target genes, we generated Hmgn1-/- mice. DNA microarray analysis of Hmgn1+/+ and Hmgn1-/- embryonic fibroblasts identified N-cadherin as a potential HMGN1 gene target. RT-PCR and western blot analysis confirmed a linkage between HMGN1 expression and N-cadherin levels. In both transformed and primary mouse embryonic fibroblasts (MEFs), HMGN1 acted as negative regulator of N-cadherin expression. Likewise, the N-cadherin levels in early embryos of Hmgn1-/- mice were higher than those of their Hmgn1+/+ littermates. Loss of HMGN1 increased the adhesiveness, motility and aggregation potential of Hmgn1-/- MEFs, a phenotype consistent with increased levels of N-cadherin protein. Re-expression of wild-type HMGN1, but not of the mutant HMGN1 protein that does not bind to chromatin, in Hmgn1-/- MEFs, decreased the levels of N-cadherin and restored the Hmgn1+/+ phenotype. These studies demonstrate a role for HMGN1 in the regulation of specific gene expression. We suggest that in MEFs, and during early mouse development, the interaction of HMGN1 with chromatin down-regulates the expression of N-cadherin.

Animals↗

PubMed2005

Histone deacetylase inhibitor pharmacodynamic analysis by multiparameter flow cytometry.

Histone deacetylase (HDAC) inhibitors are a promising new class of anticancer drug. The aim of this study was to develop a versatile and sensitive technique for the pharmacodynamic (PD) assessment of HDAC inhibitor activity as monotherapy and in combination therapy. A multiparameter flow cytometric assay was developed initially in healthy donor lymphocytes and leukemia cell lines, and then tested in peripheral blood of solid tumor patients and in bone marrow aspirates of leukemia patients on phase I trials of the HDAC inhibitor MS-275. A technique was developed that allows highly sensitive single parameter determination of HDAC inhibitor activity in as little as 50 microl of whole blood. Multiparameter analysis enabled correlation on a single cell basis of protein acetylation with biologically relevant markers including cell lineage antigens, an apoptosis marker, and PD markers of other anti-cancer agents. The level of protein acetylation can be readily detected and quantified in peripheral blood or in bone marrow aspirates by flow cytometric analysis. The technique described has significant advantages for the PD assessment of HDAC inhibitors as monotherapy and as a component of combination therapy trials.

Antineoplastic Agents↗

PubMed2004

Effects of marital transitions on changes in dietary and other health behaviours in US women.

BACKGROUND: Previous studies have indicated that married people have lower mortality and are generally healthier. Most previous studies have been cross-sectional and few studies investigated the effect of marital transition on health. With a prospective design and repeated measures of variables, we sought to analyse the temporal relation between marital transition and change in health behaviours. METHODS: We followed up 80 944 women aged 46-71 for 4 years (1992-1996). All information was self-reported. We used multivariate-adjusted linear and logistic regression models to examine the impact of changes in marital status on concomitant changes in health behaviours, controlling for potential confounders and baseline health behaviours. RESULTS: Compared with women who remained married, women who divorced/widowed had body mass index (BMI) decreases of 0.65 kg/m(2) (P < 0.001) and 0.44 kg/m(2) (P < 0.001), respectively. Compared with women who remained unmarried, women who remarried had an increase in mean BMI of 0.41 kg/m(2) (P < 0.001). Women who divorced increased physical activity by 1.23 metabolic equivalent hours (MET)/week (P = 0.07) compared with women who stayed married. Among non-smokers and past smokers, women who divorced/widowed had more than a twofold increased risk of relapsing/starting smoking (OR = 2.47, 95% CI: 1.56, 3.89; OR = 2.08, 95% CI: 1.56, 2.76, respectively) than women who stayed married. Divorced and widowed women had decreased vegetable intake relative to women who stayed married (-2.93 servings/week [P < 0.001] and -1.67 servings/week [P < 0.001], respectively). CONCLUSIONS: These patterns suggest both health-damaging and health-promoting changes accompanying divorce and widowhood, and generally health-promoting changes following remarriage.

Aged↗

PubMed2004

Prospective study of job insecurity and coronary heart disease in US women.

PURPOSE: To examine prospectively the relationship between job insecurity and incidence of coronary heart disease (CHD) among women. METHODS: We conducted the study in 36,910 women from the Nurses' Health Study, a prospective cohort of female registered nurses residing in 11 US states. These women were 46 to 71 years old, and did not have diagnosed CHD, stroke, or cancer at baseline (1992). We collected information on job insecurity in 1992 and coronary heart disease incidence between baseline (June 1, 1992) and return of the 1996 questionnaire. RESULTS: During 4 years of follow-up, we documented 154 incident cases of CHD (113 non-fatal cases of myocardial infarction (MI) and 41 CHD deaths). After adjustment for a wide array of potential confounders, the relative risk (RR) of total CHD over 2-year follow-up was 1.35 (95% CI, 0.78-2.34) and 1.04 (95% CI, 0.69-1.57) over 4-year follow-up. Job insecurity appeared to significantly increase the risk of non-fatal MI in the short term (2-year follow-up: RR=1.89, 95% CI, 1.03-3.50), though not over a longer follow-up period (RR=1.28, 95% CI, 0.82-2.00), nor fatal CHD in the short term (RR=0.49, 95% CI, 0.22-2.08). CONCLUSIONS: These data suggest that job insecurity may increase the short-term risk of non-fatal MI in women.

Aged↗

PubMed2004

Does caregiving stress affect cognitive function in older women?

Increasing numbers of women provide care to their ill spouses; however, no studies have examined possible effects of caregiving stress on cognitive function. We administered 6 tests of cognitive function to 13740 Nurses' Health Study participants aged 70-79 years. We collected information on caregiving and numerous potential confounding variables via biennial mailed questionnaires. After adjustment for potential confounders (age, education, mental health index, vitality index, use of antidepressants, and history of high blood pressure, diabetes, and heart disease), we found modest but significantly increased risks of low cognitive function on three of the cognitive tests among women who provided care to a disabled or ill spouse compared with women who did not provide any care. For example, on the TICS, a test of general cognition, the risk of a low score was 31% higher in women who provided care compared with women who did not (RR = 1.31, 95% CI 1.10, 1.56). We found a moderately increased risk of poor performance on several cognitive tests among women who provided care to their disabled or ill husbands.

Aged↗

PubMed2003

IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis.

Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. To examine whether HIF-1alpha is a factor linking inflammation and tumorigenesis, we investigated whether the HIF-1 signaling pathway was stimulated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in A549 cells. We find that IL-1beta up-regulated HIF-1alpha protein under normoxia and activated the HIF-1-responsive gene vascular endothelial growth factor (VEGF) via a pathway dependent on nuclear factor kappaB (NFkB). Interestingly, although this pathway is stimulated by upstream signaling via AKT and mTOR and requires new transcription, IL-1 mediated HIF-1alpha induction also utilizes a post-transcriptional mechanism that involves antagonism of VHL-dependent HIF-1alpha degradation, which results in increased HIF-1alpha protein stability. IL-1 mediated NFkB-dependent cyclooxygenases-2 (COX-2) expression served as a positive effector for HIF-1alpha induction. Although COX-2 inhibitors attenuated IL-1 mediated HIF-1alpha induction, prostaglandin E2 (PGE2), a physiological product of COX-2, induced HIF-1alpha protein in a dose-dependent manner. Our data, therefore, demonstrate that IL-1beta up-regulates functional HIF-1alpha protein through a classical inflammatory signaling pathway involving NFkB and COX-2, culminating in up-regulation of VEGF, a potent angiogenic factor required for tumor growth and metastasis. Thus, HIF-1 is identified as a pivotal transcription factor linking the inflammatory and oncogenic pathways.

Cell Line, Tumor↗

PubMed2003

Education, other socioeconomic indicators, and cognitive function.

The authors investigated the relation of educational attainment, husband's education, household income, and childhood socioeconomic status to cognitive function and decline among community-dwelling women aged 70-79 years. Information on exposures was self-reported, except for income (which was derived from census tract data). Between 1995 and 2000, six cognitive tests were administered to 19,319 Nurses' Health Study participants. Second assessments began in 2001 and are ongoing; as of April 2002, information was complete for 15,594 women. The authors used logistic regression to calculate multivariate-adjusted odds of a low baseline score (bottom 10%) and substantial decline (worst 10%), and linear regression was used to estimate adjusted mean differences in score and in decline across various levels of education and socioeconomic status. On a global score combining the results of all tests, women with a graduate degree had significantly decreased odds of a low baseline score (odds ratio = 0.49, 95% confidence interval: 0.36, 0.66) and decline (odds ratio = 0.65, 95% confidence interval: 0.50, 0.86) in comparison with women with a Registered Nurse diploma. Significantly lower mean scores and less mean decline were observed among women with a bachelor's or graduate degree than among women with a Registered Nurse diploma. Much weaker associations were evident for other socioeconomic variables. Thus, among well-educated women, educational attainment predicted cognitive function and decline, although other measures of socioeconomic status had little relation.

Aged↗

PubMed2003

Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells requires receptor-interacting protein-dependent nuclear factor kappa B activation.

Tumour necrosis factor alpha (TNF-alpha) binds to its receptor (TNFR1) and activates both death- and inflammation/survival-related signalling pathways. The inflammation and survival-related signalling cascade results in the activation of the transcription factor, nuclear factor kappa B (NF-kappa B) and requires recruitment of receptor-interacting protein (RIP) to TNFR1. The indispensable role of RIP in TNF-induced NF-kappa B activation has been demonstrated in RIP(-/-) mice and in cell lines derived from such mice. In the present study, we show that the TNF-alpha-induced accumulation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) protein in normoxic cells is RIP-dependent. Exposing fibroblasts derived from RIP(-/-) mice to either cobalt or PMA resulted in an equivalent HIF-1 alpha induction to that seen in RIP(+/+) fibroblasts. In contrast, RIP(-/-) cells were unable to induce HIF-1 alpha in response to TNF-alpha. Further, transient transfection of NIH 3T3 cells with an NF-kappa B super-repressor plasmid (an inhibitor of NF-kappa B activation) also prevented HIF-1 alpha induction by TNF-alpha. Surprisingly, although HIF-1 alpha mRNA levels remained unchanged after induction by TNF, induction of HIF-1 alpha protein by the cytokine was completely blocked by pretreatment with the transcription inhibitors actinomycin D and 5,6-dichlorobenzimidazole riboside. Finally, TNF failed to induce both HIF-1 alpha, made resistant to von Hippel-Lindau (VHL), and wild-type HIF-1 alpha transfected into VHL(-/-) cells. These results indicate that HIF-1 alpha induction by TNF-alpha in normoxic cells is mediated by protein stabilization but is nonetheless uniquely dependent on NF-kappa B-driven transcription. Thus the results describe a novel mechanism of HIF-1 alpha up-regulation and they identify HIF-1 alpha as a unique component of the NF-kappa B-mediated inflammatory/survival response.

Animals↗

PubMed2003

Caregiving and risk of coronary heart disease in U.S. women: a prospective study.

BACKGROUND: A growing number of women provide care to disabled or ill relatives. Many studies have linked caregiving to psychiatric morbidity, lower perceived health status, elevated blood pressure, and poorer immune function. However, no studies have examined the association between caregiving and cardiovascular disease incidence. METHODS: We conducted the study in 54,412 women from the Nurses' Health Study, a prospective cohort of female registered nurses residing in 11 U.S. states. These women were aged 46 to 71 years and did not have diagnosed coronary heart disease (CHD), stroke, or cancer at baseline (1992). We collected information on caregiving responsibilities in 1992 and coronary heart disease between baseline (June 1, 1992) and return of the 1996 questionnaire. RESULTS: During 4 years of follow-up, we documented 321 incident cases of CHD (231 nonfatal cases of myocardial infarction and 90 CHD deaths). In multivariate analyses controlling for age, smoking, exercise, alcohol intake, body mass index, history of hypertension, diabetes mellitus, and other covariates, caregiving for disabled or ill spouse for > or =9 hours per week was associated with increased risk of CHD (RR, 1.82; 95% confidence interval, 1.08-3.05). However, caregiving for disabled or ill parents or disabled or ill others was not significantly associated with increased risks of CHD. CONCLUSION: These data indicate that high levels of caregiving burden for ill spouses may increase the risk of CHD among women.

Aged↗

PubMed2003

Caregiving to children and grandchildren and risk of coronary heart disease in women.

OBJECTIVES: We examined the relationship between burden of providing care to non-ill children and grandchildren and incidence of coronary heart disease (CHD) among women. METHODS: A prospective cohort study was conducted as part of the Nurses' Health Study among 54,412 women aged 46 to 71 years who were registered nurses. Women answered questions about their child care responsibilities. RESULTS: We documented 321 incident cases of CHD during 4 years of follow-up. Multivariate analyses showed that caring for non-ill children 21 hours or more per week and caring for non-ill grandchildren 9 hours or more per week (vs no caregiving) were associated with an increased risk of CHD (relative risks were 1.59 and 1.55, respectively). CONCLUSIONS: High levels of care provision to grandchildren (and possibly children) may increase the risk of CHD among women.

Aged↗

PubMed2002

Microtubule disruption utilizes an NFkappa B-dependent pathway to stabilize HIF-1alpha protein.

Hypoxia-inducible factor (HIF)-1alpha levels are elevated in normoxic cells undergoing physiological processes involving large scale microtubule reorganization, such as embryonic development, wound healing, and tumor cell metastasis. Although alterations in microtubules affect numerous cellular responses, no data have yet implicated microtubule dynamics in HIF-1alpha regulation. To investigate the effect of microtubule change upon HIF-1alpha regulation, we treated cells with the microtubule-depolymerizing agents (MDAs) colchicine, vinblastine or nocodazole. We demonstrate that these agents are able to induce transcriptionally active HIF-1. MDA-mediated induction of HIF-1alpha required microtubule depolymerization, since HIF-1alpha levels were unchanged in cells treated with either the microtubule-stabilizing agent paclitaxel, or an inactive form of colchicine, or in colchicine-resistant cells. HIF-1 induction was dependent upon cellular transcription, as transcription inhibitors abrogated HIF-1alpha protein up-regulation. The ability of transcriptional inhibitors to interfere with HIF-1alpha accumulation was specific to the MDA-initiated pathway, as they were ineffective in preventing hypoxia-mediated HIF-1 induction, which occurs by a distinct post-translational pathway. Moreover, we provide evidence implicating a requirement for NFkappaB transcription in the HIF-1 induction mediated by MDAs. The ability of MDAs to induce HIF-1alpha is dependent upon activation of NFkappaB, since inhibition of NFkappaB either pharmacologically or by transfection of an NFkappaB super-repressor plasmid abrogated this induction. Collectively, these data support a model in which NFkappaB is a focal point for the convergence of MDA-mediated signaling events leading to HIF-1 induction, thus revealing a novel aspect of HIF-1alpha regulation and function.

Animals↗

PubMed2002

Regulation of leukemic cell adhesion, proliferation, and survival by beta-catenin.

In epithelial cells beta-catenin plays a critical role as a component of the cell-cell adhesion apparatus and as a coactivator of the TCF/LEF (T-cell transcription factor/lymphoid enhancer binding factor) family of transcription factors. Deregulation of beta-catenin has been implicated in the malignant transformation of cells of epithelial origin. However, a function for beta-catenin in hematologic malignancies has not been reported. beta-Catenin is not detectable in normal peripheral blood T cells but is expressed in T-acute lymphoblastic leukemia cells and other tumor lines of hematopoietic origin and in primary lymphoid and myeloid leukemia cells. beta-Catenin function was examined in Jurkat T-acute lymphoblastic leukemia cells. Overexpression of dominant-negative beta-catenin or dominant-negative TCF reduced beta-catenin nuclear signaling and inhibited Jurkat proliferation and clonogenicity. Similarly, these constructs inhibited proliferation of K562 and HUT-102 cells. Reduction of beta-catenin expression with beta-catenin antisense down-regulated adhesion of Jurkat cells in response to phytohemagglutinin. Incubation of Jurkat cells with anti-Fas induced caspase-dependent limited proteolysis of beta-catenin N- and C-terminal regions and rapid redistribution of beta-catenin to the detergent-insoluble cytoskeleton, concomitant with a marked decline in nuclear beta-catenin signaling. Fas-mediated apoptosis was potentiated by inhibition of beta-catenin nuclear signaling. The data suggest that beta-catenin can play a significant role in promoting leukemic cell proliferation, adhesion, and survival.

Apoptosis↗

PubMed2002

A prospective study of job strain and coronary heart disease in US women.

BACKGROUND: Previous studies of job strain and coronary heart disease (CHD) in men have established job strain as a predictor of CHD risk. Despite the wealth of convincing evidence in men for an association between job strain and CHD, data in women remain sparse. METHODS: We prospectively evaluated the relation between job strain and CHD risk in the Nurses' Health Study. In this analysis, we followed a sample of 35 038 US female nurses aged 46-71 years, who completed questions about job strain in 1992 and who were free of diagnosed CHD, stroke, and cancer at baseline. The main outcome measure was the incidence of CHD occurring between baseline (1 June 1992) and 31 May 1996. RESULTS: During 4 years of follow-up, we documented 146 incident cases of CHD (108 non-fatal cases of myocardial infarction and 38 CHD deaths). No evidence was found for a relationship between job strain and risk of CHD. In multivariate analyses controlling for age, smoking, alcohol intake, body mass index, history of hypertension, diabetes mellitus, and other covariates, women in high strain jobs did not have an increased risk of CHD (relative risk [RR] = 0.71, 95% CI: 0.42-1.19) compared with women in low strain jobs. Neither women in passive jobs (RR = 1.08, 95% CI: 0.69-1.68) nor those in active jobs (RR = 0.91, 95% CI: 0.54-1.53) had an increased risk of CHD. CONCLUSIONS: Job strain was not related to an increase in the incidence of CHD in the present cohort of nurses.

Aged↗