H Huynh

National Cancer Centre Singapore, Singapore

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Publications (40)182.6 Total impact

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    ABSTRACT: Background & aims: Preclinical studies have demonstrated the additive effect of rapamycin with bevacizumab for hepatocellular carcinoma treatment. We conducted a Phase 1 study to evaluate the safety and pharmacokinetics of the combination in patients with hepatocellular carcinoma. Methods: Adult participants with advanced hepatocellular carcinoma received intravenous bevacizumab (5mg/kg every 14 days) and oral rapamycin (1-6 mg/day; 3+3 dose escalation design). Computed tomography assessed tumour response and treatment safety. Pharmacokinetics assessment established rapamycin blood concentrations pre- and post-dose. Dynamic contrast-enhanced computed tomography analysed the tumour region for blood flow, permeability surface area product, fractional intravascular blood volume and extracellular-extravascular volume. Results: Twenty-four participants were treated. There were two dose limiting toxicities with rapamycin 5mg: grade 3 thrombocytopenia and grade 3 mucositis. The maximally tolerated dose of rapamycin was 4 mg. Adverse events (grade 1-2) included hyperglycaemia (83%), thrombocytopenia (75%), fatigue (46%), mucositis (46%), anorexia (42%), diarrhoea (33%) and proteinuria (12.5%). Of 20 evaluable participants, one reached complete response that lasted 4.5 months, two reached partial response, 14 reached stable disease and three had progressive disease. Median overall survival was 9.4 months; progression-free survival was 5.5 months. Dose level and steady state area under the concentration time curve for hour zero to infinity of rapamycin correlated inversely with blood flow rate and change in permeability-surface area. After 22 days of treatment, there were significant reductions from baseline in blood flow rate, permeability-surface area and fractional intracellular blood volume. Conclusions: The recommended Phase 2 dose of rapamycin is 4 mg in combination with bevacizumab. Evidence of anti-vascular activity was observed together with promising clinical activity.
    European journal of cancer (Oxford, England: 1990) 12/2012; 49(5). DOI:10.1016/j.ejca.2012.11.008 · 5.42 Impact Factor
  • K C Sia · H Huynh · N Chinnasamy · K M Hui · P Y P Lam ·
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    ABSTRACT: Hepatocellular carcinoma (HCC) is usually refractory to the available treatments. For cancer gene therapy purposes, real-time imaging of therapeutic gene expression is of great importance because there are multiple factors that modulate the therapeutic gene expression in a complex tumor microenvironment. As a consequence, multiple doses of therapeutic viral vectors may be required for improved efficacy. In the present study, the luciferase reporter gene and the yeast cytosine deaminase (yCD) genes were bicistronically expressed using the foot-and-mouth disease virus 2A peptide under the regulation of the cytomegalovirus (CMV) promoter. The effectiveness of the yCD/5-FC (5-fluorocytosine) killing efficacy mediated by the herpes simplex virus type 1 (HSV-1) amplicon viral vector was shown using HCC and non-HCC cell lines in vitro. In addition, in vivo experiment also showed tumor regression of a primary HCC 26-1004 tumor xenograft in tumor expressing high levels of the yCD gene (as determined by noninvasive imaging) after intratumoral injection of 1.5 × 10(6) TU HGCX-L2C HSV-1 amplicon viral vector and 5-FC administration. The HSV-1 amplicon viral vector coupled with the yCD/5-FC prodrug activated suicide gene could potentially be of use in clinical gene therapy for HCC.
    Gene therapy 09/2011; 19(5):532-42. DOI:10.1038/gt.2011.131 · 3.10 Impact Factor
  • H Huynh · S P Choo · H C Toh · W M Tai · A Y F Chung · P K H Chow · R Ong · K C Soo ·
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest malignancy. Sorafenib has demonstrated 44% survival advantage over placebo and has emerged as a standard of care in advanced HCC. The therapeutic effects of sorafenib are however transient and hence additional treatment options are warranted. In this study, we aimed to compare the efficacy of sunitinib relative to sorafenib, two potent inhibitors of protein tyrosine kinases involved in tumor growth, metastasis, or angiogenesis. We reported that sorafenib and sunitinib suppressed tumor growth, angiogenesis, cell proliferation, and induced apoptosis in both orthotopic and ectopic models of HCC. However, the antitumor effect of 50 mg/kg sorafenib was greater than that of 40 mg/kg sunitinib. Sorafenib inhibited p-eIF4E Ser209, p-p38 Thr180/Tyr182 and reduced survivin expression. This was not seen with sunitinib. In addition, the antitumor and apoptotic effects of sorafenib, which are associated with upregulation of fast migrating Bim and ASK1 and downregulation of survivin, were greater than that of sunitinib. These observations explained in part the apparent superior anti-tumor activity of sorafenib compared to sunitinib. In conclusion, sunitinib demonstrated an inferior anti-tumor activity compared to sorafenib in ectopic and orthotopic models of human HCC. It remains to be seen whether such observations would be recapitulated in humans.
    Current cancer drug targets 08/2011; 11(8):944-53. DOI:10.2174/156800911797264716 · 3.52 Impact Factor
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    J S P Yuen · M Y Sim · H G Siml · T W Chong · W K O Lau · C W S Cheng · H Huynh ·
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    ABSTRACT: It is widely recognised that sorafenib inhibits a range of molecular targets in renal cell carcinoma (RCC). In this study, we aim to use patient-derived RCC xenografts to delineate the angiogenic and non-angiogenic molecular targets of sorafenib therapy for advanced RCC (aRCC). We successfully generated three patient RCC-derived xenografts in severe combined immunodeficient mice, consisting of three different RCC histological subtypes: conventional clear cell, poorly differentiated clear cell RCC with sarcomatoid changes, and papillary RCC. This study also used clear cell RCC cells (786-0/EV) harbouring mutant VHL to investigate the clonogenic survival of cells transfected with survivin sense and antisense oligonucleotides. All three xenografts retain their original histological characteristics. We reported that sorafenib inhibited all three RCC xenograft lines regardless of histological subtypes in a dose-dependant manner. Sorafenib-induced growth suppression was associated with not only inhibition of angiogenic targets p-PDGFR-β, p-VEGFR-2, and their downstream signalling pathways p-Akt and p-ERK, cell cycle, and anti-apoptotic proteins that include cyclin D1, cyclin B1, and survivin but also upregulation of proapoptotic Bim. Survivin knockdown by survivin-specific antisense-oligonucleotides inhibited colony formation and induced cell death in clear cell RCC cells. This study has shed light on the molecular mechanisms of sorafenib in RCC. Inhibition of non-angiogenic molecules by sorafenib could contribute in part to its anti-tumour activities observed in vivo, in addition to its anti-angiogenic effects.
    British Journal of Cancer 03/2011; 104(6):941-7. DOI:10.1038/bjc.2011.55 · 4.84 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest primary neoplasm. Since HCC is a particularly vascular solid tumor, we determined the antitumor and antiangiogenic activities of sunitinib malate, a potent inhibitor of two receptors involved in angiogenesis - vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). In the present study, we reported that treatment of HepG2 and SK-Hep-1 cells with sunitinib led to growth inhibition and apoptosis in a dose-dependent fashion. Sunitinib inhibited phosphorylation of VEGFR-2 at Tyr951 and PDGFR-beta at Tyr1021 both in vitro and in vivo. Sunitinib also suppressed tumor growth of five patient-derived xenografts. Sunitinib-induced tumor growth inhibition was associated with increased apoptosis, reduced microvessel density and inhibition of cell proliferation. This study provides a strong rationale for further clinical investigation of sunitinib in patients with hepatocellular carcinoma.
    Current cancer drug targets 09/2009; 9(6):738-47. · 3.52 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth most common and third deadliest primary neoplasm. Since HCC is a particularly vascular solid tumor, we determined the antitumor and antiangiogenic activities of sunitinib malate, a potent inhibitor of two receptors involved in angiogenesis - vascular endothelial growth factor receptor (VEGFR) and plateletderived growth factor receptor (PDGFR). In the present study, we reported that treatment of HepG2 and SK-Hep-1 cells with sunitinib led to growth inhibition and apoptosis in a dose-dependent fashion. Sunitinib inhibited phosphorylation of VEGFR-2 at Tyr951 and PDGFR-β at Tyr1021 both in vitro and in vivo. Sunitinib also suppressed tumor growth of five patient-derived xenografts. Sunitinib-induced tumor growth inhibition was associated with increased apoptosis, reduced microvessel density and inhibition of cell proliferation. This study provides a strong rationale for further clinical investigation of sunitinib in patients with hepatocellular carcinoma.
    Current Cancer Drug Targets 08/2009; 9(6):738-747. DOI:10.2174/156800909789271530 · 3.52 Impact Factor
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    ABSTRACT: Our previous studies have shown that transgene expression could be targeted to proliferating cells when cell cycle transcriptional regulatory elements were incorporated into herpes simplex virus type 1 (HSV-1) amplicon backbone vectors. In the study reported here, we further demonstrated the transcriptional activation of transgene expression in association with the onset of cellular proliferation using the mouse partial hepatectomy model. Moreover, transcriptional regulation could be rendered specific to human hepatocellular carcinoma (HCC) cells by inserting the chimeric gene Gal4/NF-YA under the regulation of the HCC-specific hybrid promoter. The hybrid promoter, which consists of four copies of the apolipoprotein E (ApoE) enhancer element inserted upstream of the human alpha1-antitrypsin(hAAT) promoter, induced an higher level of transcription than other liver-specific promoters such as alpha-fetoprotein (AFP) and albumin (Alb) promoter. As a consequence, the enhancement of tissue-specific expression in the context of Gal4/NF-YA fusion proteins enabled the monitoring of transgene expression using a bioluminescence imaging system. Furthermore, these vectors have been shown to be non-toxic and exhibited potent infectivity for proliferating primary HCC cells and HCC cell lines. Together, these results demonstrated that the new hybrid vectors could provide options for the design of safe and efficient systemic gene therapeutic strategies for human HCC.
    Molecular Therapy 06/2007; 15(6):1129-36. DOI:10.1038/sj.mt.6300165 · 6.23 Impact Factor
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    C K Ong · C Leong · P H Tan · T Van · H Huynh ·
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide. OKL38 is a pregnancy-induced growth inhibitory gene and its expression is lost in various breast cancer cell lines and kidney tumor. To determine the role of OKL38 expression in HCC, we investigated its expression in various HCC samples and liver cancer cell lines. Western blot analysis revealed that OKL38 protein was absent or reduced in 64.2% (18 of 28) of the HCCs examined and four liver cancer cell lines. Immunohistochemistry study demonstrated that OKL38 protein was undetectable in 41.3% (38 of 92) of HCC, whereas 39.1% (36 of 92) of HCC showed low expression of the protein. Lost or reduced expression level of OKL38 protein was significantly correlated to high tumor stages in HCC (P=0.0042). Overexpression of the OKL38 caused cell death in Chang liver cells. 5' Untranslated region (5'UTR) deletion studies demonstrated that OKL38 was downregulated via translation suppression associated with the 5'UTR of its mRNA. Taken together, the 5'UTRs of OKL38 might play an important role in downregulation of its protein and the absence of OKL38 could lead to the development or progression of HCC.
    Oncogene 03/2007; 26(8):1155-65. DOI:10.1038/sj.onc.1209896 · 8.46 Impact Factor
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    C T C Leong · C K Ong · S K Tay · H Huynh ·
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    ABSTRACT: Ovarian cancer is currently the second leading cause of gynecological malignancy and cisplatin or cisplatin-based regimens have been the standard of care for the treatment of advance epithelial ovarian cancers. However, the efficacy of cisplatin treatment is often limited by the development of drug resistance either through the inhibition of apoptotic genes or activation of antiapoptotic genes. We have previously reported the overexpression of human UO-44 (HuUO-44) in ovarian cancers and the HuUO-44 antisera markedly inhibited NIH-OVCAR3 ovarian cancer cell attachment and proliferation (Oncogene 23: 5707-5718, 2004). In the present study, we observed through the cancer cell line profiling array that the expression of HuUO-44 was suppressed in the ovarian cancer cell line (SKOV-3) after treatment with several chemotherapeutic drugs. Similarly, this suppression in HuUO-44 expression was also correlated to the cisplatin sensitivity in two other ovarian cancer cell lines NIH-OVCAR3 and OV-90 in a dose-dependent manner. To elucidate the function of HuUO-44 in cisplatin chemoresistance in ovarian cancer cell, small interfering RNAs (siRNAs) were employed to mediate HuUO-44 silencing in ovarian cancer cell line, NIH-OVCAR3. HuUO-44 RNA interference (RNAi) resulted in the inhibition of cell growth and proliferation. Importantly, HuUO-44 RNAi significantly increased sensitivity of NIH-OVCAR3 to cytotoxic stress induced by cisplatin (P<0.01). Strikingly, we have also demonstrated that overexpression of HuUO-44 significantly conferred cisplatin resistance in NIH-OVCAR3 cells (P<0.05). Taken together, UO-44 is involved in conferring cisplatin resistance; the described HuUO-44-specific siRNA oligonucleotides that can potently silence HuUO-44 gene expression may prove to be valuable pretreatment targets for antitumor therapy or other pathological conditions that involves aberrant HuUO-44 expression.
    Oncogene 02/2007; 26(6):870-80. DOI:10.1038/sj.onc.1209836 · 8.46 Impact Factor
  • T H Nguyen · C K Ong · E Wong · C T Leong · L Panasci · H Huynh ·
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    ABSTRACT: 2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) has been used to treat patients with advanced solid tumours. However, the molecular mechanisms are not well understood. In the present study, we report that SarCNU inhibited proliferation of human HK-1 and CNE-2 nasopharyngeal carcinoma (NPC) in vivo and in vitro. In vitro study showed that wild-type p53 HK-1 cells were 3-fold more sensitive to SarCNU than p53 mutant CNE-2 cells. G2/M arrest, reduction in p21(Cip1/Waf1) and inactivation of cellular cdc-2 activity were seen in both SarCNU-treated HK-1 and CNE-2 cells. Upregulation of p53, phosphorylated p53 at Ser15 and biochemical markers for apoptosis, such as cleaved caspase-3, cleaved caspase-7 and cleaved PARP, were observed in SarCNU-treated HK-1 but not CNE-2 cells. The levels of cyclin B1, Wee1 and phosphorylated cdc-2 but not total cdc-2 in HK-1 cells were significantly reduced by SarCNU treatment. In contrast to HK-1 cells, decrease in total cdc-2 but increase in phosphorylated cdc-2 at Tyr15, cyclin B1 and Wee1 was observed in CNE-2 cells treated with SarCNU. Introduction of mutant p53 into HK-1 cells resulted in growth enhancement in vivo and increased resistance to SarCNU-induced apoptosis in vitro. Furthermore, CNE-2 cells transfected with wild-type p53 became susceptible to SarCNU-induced apoptosis in vitro but not their growth rate in vivo. The data indicate that in NPC cells SarCNU-induced apoptosis was p53-dependent while SarCNU-induced G2/M arrest was mediated by altering the levels of cyclin B1-cdc-2 complex and phosphorylation of cdc-2 at Tyr15 resulting in inactivation of cellular cdc-2 activity. Our data suggest a potential use of SarCNU in the treatment of NPC.
    International Journal of Oncology 11/2005; 27(4):1131-40. DOI:10.3892/ijo.27.4.1131 · 3.03 Impact Factor
  • H Huynh · P T Do · T H Nguyen · P Chow · P H Tan · T H Quach · T Van · K C Soo · E Tran ·
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignancies in Southeast Asia. Hyperphosphorylation of retinoblastoma (pRB) by cyclin/CDKs in G1/S transition is required for its inactivation and cell cycle progression. In the present study, we report that phosphorylation of pRB at Ser780 and Ser795 was detected in 71% (33 of 46) and 63% (29 of 46) of HCCs examined respectively. pRB protein was undetectable in 13% (6 of 46) of HCCs examined. Phosphorylated pRB was localized in the nuclei of hepatocarcinoma cells. Benign hepatocytes exhibited very weakly or no nuclear staining for phosphorylated pRB. Over-expression of E2F-1, cyclin D1, Cdk-2, Cdk-4 and cyclin A was found in 64% (30 of 46), 43% (26 of 46), 28% (11 of 46), 71% (33 of 46) and 63% (29 of 46) of HCCs examined respectively and this was correlated with elevation of ERK. Treatment of HepG2 cells with MEK1/2 inhibitor U0126 resulted in cell cycle arrest, downregulation of cyclin D1 and Cdk-2 expression and inhibition of pRB phosphorylation at Ser780 and Ser795. Ectopic expression of activated MEK1 in HepG2 cells increased cyclin D1 and Cdk-2 expression, phosphorylation of pRB at Ser780 and Ser795, and percentage of cells in S phase. Our data indicate that activated ERK plays an important role in cyclin D1 and Cdk-2 expression and phosphorylation of pRB at Ser780 and Ser795 in liver cancer cells.
    International Journal of Oncology 01/2005; 25(6):1839-47. DOI:10.3892/ijo.25.6.1839 · 3.03 Impact Factor
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    ABSTRACT: Dietary phytochemicals have been shown to be protective against various types of cancers. However, the precise underlying protective mechanisms are poorly understood. In the present study, we report that treatment of A549 cells with quercetin resulted in a dose-dependent reduction in cell viability and DNA synthesis with the rate of apoptosis equivalent to 1.2 +/- 0.8, 6.3 +/- 0.9, 16.5 +/- 1.5, 36.4 +/- 2.6 and 42.5 +/- 5.8% on treatment with 0.1% dimethylsulfoxide, 14.5, 29.0, 43.5 and 58.0 micro M quercetin, respectively. Concomitantly, quercetin treatments led to a 1.1-, 1.1-, 2.5- and 3.5-fold increase in Bax. Similar elevations were also observed in Bad, which increased 1.1-, 2.1-, 2.2- and 2.3-fold, respectively, as compared with control. While Bcl-2 was decreased by 30%, Bcl-x(L) was elevated in a dose-dependent fashion. Quercetin also induced the cleavage of caspase-3, caspase-7 and PARP (poly ADP-ribose polymerase). While Akt-1 and phosphorylated Akt-1 were inhibited, the extracellular signal-regulated kinase (ERK) was phosphorylated following quercetin treatment in a dose-dependent fashion. Phosphorylation of ERK and c-Jun occurred at 3 h and was sustained over 14 h. Phosphorylation of MEK1/2 was increased in concordance with ERK activation. Quercetin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and cleavage of caspase-3 occurred 6 h after quercetin exposure and before cleavage of caspase-7 and PARP was detected. Inhibition of MEK1/2 but not PI-3 kinase, p38 kinase or JNK abolished quercetin-induced phosphorylation of c-Jun, cleavage of caspase-3 and -7, cleavage of PARP and apoptosis. Inhibition of caspase activation completely blocked quercetin-induced apoptosis. Expression of constitutively activated MEK1 in A549 cells led to activation of caspase-3 and apoptosis. The results suggest that in addition to inactivation of Akt-1 and alteration in the expression of the Bcl-2 family of proteins, activation of MEK-ERK is required for quercetin-induced apoptosis in A549 lung carcinoma cells.
    Carcinogenesis 06/2004; 25(5):647-59. DOI:10.1093/carcin/bgh052 · 5.33 Impact Factor
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    ABSTRACT: A vast variety of naturally occurring substances have been shown to protect against experimental carcinogenesis and an increasing amount of evidence suggests that kaempferol may have cancer chemopreventative properties. However, the precise underlying protective mechanisms are poorly understood. To elucidate these mechanisms, we challenged human lung cancer cell line A549 with kaempferol and investigated its effects upon cellular growth and signal transduction pathways. Treatment of A549 cells with kaempferol resulted in a dose- and time-dependent reduction in cell viability and DNA synthesis with the rate of apoptosis equivalent to 0.9+/-0.5, 5.2+/-1.5, 16.8+/-2.0, 25.4+/-2.6, and 37.8+/-4.5% on treatment with 0, 17.5, 35.0, 52.5, and 70.0 microM kaempferol, respectively. Concomitantly, kaempferol treatments led to a 1.2-, 2.7-, 3.3-, and 3.4-fold increase in Bax. Similar elevations were also observed in Bad which increased 1.2-, 3.3-, 3.7-, and 4.7-fold, respectively, as compared to control. Bcl-2 and Bcl-xL expression were inhibited in a dose-dependent fashion. While the Akt-1 and phosphorylated Akt-1 were inhibited, the mitogen-activated protein kinase (MAPK) was activated upon kaempferol treatment. Kaempferol induced apoptosis was associated with the cleavage of caspase-7 and poly ADP-ribose polymerase (PARP). Inhibition of MEK1/2 but not PI-3 kinase blocked kaempferol-induced cleavage of caspase-7, PARP cleavage, and apoptosis. The results suggest that inactivation of Akt-1 and alteration of Bcl-2 family of proteins are not sufficient for kaempferol to induce apoptosis and activation of MEK-MAPK is a requirement for kaempferol-induced cell death machinery in A549 cells.
    Journal of Cellular Physiology 10/2003; 197(1):110-21. DOI:10.1002/jcp.10340 · 3.84 Impact Factor
  • T.T. Phan · P See · E Tran · T.T.T. Nguyen · S.Y. Chan · S.T. Lee · H Huynh ·
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    ABSTRACT: Keloids are characterized by abnormal proliferation of fibroblasts and overproduction of collagen. Insulin-like growth factor (IGF)-I is mitogenic for fibroblasts and a stimulatory factor for collagen synthesis. We have assessed the in vitro effects of quercetin on proliferation, collagen synthesis and the expression of the IGF system in keloid-derived fibroblasts. Fibroblasts were isolated from earlobe keloids and exposed to quercetin at different concentrations. The inhibitory effects of quercetin on fibroblast proliferation were assayed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Western and Northern blot analyses. Quercetin inhibited keloid fibroblast (KF) proliferation in a dose-dependent manner. Significant growth inhibition was observed on day 2 of culture. The dose required for 50% growth inhibition was approximately 25 microg mL-1. Collagen 1 expression was significantly decreased while collagen 3 was almost undetectable following quercetin treatment. Basal levels of IGF-I receptor (IGF-IR) beta subunits, p85 subunit of phosphatidylinositol 3-kinase, c-Raf, phospho-Raf-1, phospho-MEK 1/2, phospho-mitogen-activated protein kinase, phospho-Elk-1 and phospho-Akt-1 were significantly reduced when KF cells were exposed to quercetin for 24 h. Blocking IGF-IR activity with IGF-IR antibody or neutralizing endogenous IGF-I activity with IGF-I antibody led to significant growth inhibition suggesting the role of IGF-I in regulation of KF proliferation. Because the IGF system plays an important part in fibroblast cell proliferation and collagen production, the described activities of quercetin on the IGF system and collagen expression may provide a novel approach for the use of quercetin in treatment and/or prevention of hypertrophic scar and keloid.
    British Journal of Dermatology 04/2003; 148(3):544-52. DOI:10.1046/j.1365-2133.2003.05174.x · 4.28 Impact Factor
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    ABSTRACT: We have previously reported the possible role of the insulin-like growth factor-I (IGF-I) system of mitogens in the development of detrusor smooth muscle hyperplasia and hypertrophy after spinal cord injury. We evaluated the in vivo effects of the anti-growth factor somatostatin analogue octreotide on the IGF-I system as well as subsequent changes in bladder smooth muscle hypertrophy and function after spinal cord injury in rats. Included in this study were 90 adult female Sprague-Dawley rats weighing 200 to 250 gm. Of the rats 18 served as sham operated controls, while the remaining 72 underwent were spinal cord transection at the level of the T10 vertebra. The spinalized animals were randomly divided into 4 equal groups of 18, of which 1 group served as paraplegic controls. The other 3 groups received octreotide (60 microgram. daily for 4 weeks) delivered via a subcutaneously implanted osmotic pump immediately, 2 and 4 weeks after spinal cord injury. At the end of the experiment (6 to 8 weeks) each group of animals was subdivided into 2 subgroups of 9. In the first group filling cystometrography was done, while in the second subgroup wet bladder weight was estimated and Northern blot analysis was performed. Mean wet bladder weight plus or minus standard deviation in sham operated and paraplegic controls was 0.11 +/- 0.01 and 0.64 +/- 0.33 gm., respectively (p <0.05). The increase in bladder weight in paraplegic controls was associated with over expression of the IGF-I gene and with marked suppression of IGF binding proteins-3 and 5 compared with sham operated controls. On the other hand, mean wet bladder weight in the animals that received octreotide immediately after spinal cord injury was 0.17 +/- 0.02 gm., which was associated with a dramatic decrease in IGF-I gene expression and increased expression of IGF binding proteins-3 and 5. Mean cystometric bladder capacity in paraplegic controls was 0.48 +/- 0.18 ml. with an associated voiding pressure of 71 +/- 13 cm. water. All paraplegic controls showed detrusor hyperreflexia. In animals that received octreotide immediately after spinal cord injury mean cystometric bladder capacity was 2.49 +/- 1.75 ml. with an associated voiding pressure of 32 +/- 7 cm. water. Detrusor hyperreflexia disappeared in 88.89% of the rats in this group. There were less marked changes in bladder weight (mean 0.24 and 0.29 +/- 0.3 gm.), IGF-I gene expression and its binding proteins and urodynamic parameters when the drug was given 2 and 4 weeks, respectively, after spinal cord injury. Modulating the IGF-I system of mitogens in detrusor smooth muscle with consequently decreased bladder hypertrophy and improved urodynamic behavior in spinal cord injured animals using somatostatin analogue could be a possible therapeutic modality in patients with spinal cord injury.
    The Journal of Urology 09/2002; 168(3):1253-8. DOI:10.1097/01.ju.0000023415.33250.a8 · 4.47 Impact Factor
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    H Huynh · L Alpert · M A Alaoui-Jamali · CY Ng · T W Chan ·
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    ABSTRACT: Prostate cancer is the most diagnosed invasive malignancy in males. Androgens and oestrogens have been implicated in the pathogenesis of prostate cancer. We report herein that the pure anti-oestrogen ICI 182,780 (ICI) reduces Ki-67 labelling index and IGF-I receptor levels in rat prostate. Increase of IGF-I mRNA and IGF-binding protein 3 (IGFBP-3) accumulation occur without any effect on prostate weight. Finasteride significantly decreases prostate weight and inhibits IGF-I gene expression. IGFBP-3 mRNA, Akt and phospho-Akt are not affected by finasteride. Co-administration of ICI plus finasteride reduces prostate weight by approximately 50% and causes acinar dilation with decreased luminal epithelial cell thickness. The acinar epithelial cells became atrophic and inactive with minimal cytoplasm. We also demonstrate a synergistic effect of ICI and finasteride on induction of IGFBP-3 accumulation and inhibition of Akt phosphorylation. Because the IGF and IGFBP-3 system plays an important role in prostate epithelial cell proliferation, apoptosis and tumour progression, the inhibitory effects of finasteride and ICI on IGF system may contribute to their anti-proliferative activity. These observations support a potential use of ICI in conjunction with finasteride in the prevention and/or treatment of prostate cancer.
    Journal of Endocrinology 11/2001; 171(1):109-18. · 3.72 Impact Factor
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    H Huynh ·

    Journal of Endocrinology 10/2001; 171(1):109-118. DOI:10.1677/joe.0.1710109 · 3.72 Impact Factor
  • T W Chan · G Mark · H Huynh ·
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    ABSTRACT: Epidemiological studies have shown that early first pregnancy is associated with a life-long reduction in breast cancer risk. The terminal differentiation associated with pregnancy and lactation has been proposed as a mechanism underlying the protective effect of pregnancy. We report that treatment of rats with ICI 182,780 (ICI) caused a marked reduction in epithelial cells and Ki-67 labelling index as compared to controls and testosterone enanthate-treated (TE) mammary glands. TE increased the Ki-67 labelling index, stimulated lobuloalveolar and ductal growth, as well as the secretory activity of acinar cells. Co-administration of TE and ICI resulted in a reduction in Ki-67 labelling index. Mammary epithelial cells became differentiated, resembling that observed at the end of pregnancy and during lactation as indicated by marked increase in secretory activity, lipid accumulation and presence of basal nuclei. The expression of differentiation markers such as whey acidic protein, mammary derived growth inhibitor, alpha-casein and beta-casein was detected only in TE plus ICI treated mammary tissues. Unlike TE, ICI caused a significant reduction in DMBA-induced tumour incidence, number of tumour bearing and tumour size. Tumour incidence was reduced to 8% when both ICI and TE were co-administered. Our data provide the novel molecular interactions between the estrogen and androgen in regulation of mammary growth and differentiation. These observations may give insight into novel actions of ICI and TE on breast differentiation and protection against carcinogenesis which may be useful in designing novel strategies for cancer prevention and/or treatment based on maximizing mammary epithelial cell differentiation.
    International Journal of Oncology 09/2001; 19(2):263-9. DOI:10.3892/ijo.19.2.263 · 3.03 Impact Factor
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    H Huynh · C Y Ng · C K Ong · K B Lim · T W Chan ·
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    ABSTRACT: Growth factors and growth inhibitors play crucial roles in the growth regulation and differentiation of mammary epithelial cells. Studies have shown that during pregnancy, with the onset of terminal differentiation, there is a dramatic decrease in the proliferation of the mammary epithelial cells. Here we report the cloning and characterization of a novel pregnancy-induced cDNA, OKL38, from a human ovarian cDNA library. This cDNA encodes for a protein of approximately 34.5 kDa. Tissue distribution studies through Northern analyses revealed the ubiquitous nature of OKL38 transcripts in most tissues, with the highest levels observed in the ovary, kidney, and liver. The onset and advancement of pregnancy also gave rise to a concomitant increase in OKL38 gene expression. In situ hybridization revealed that OKL38 mRNA was further detected in mammary secretory epithelial cells. However, low levels of OKL38 transcripts were observed in the various human breast cancer cell lines studied and were barely detectable in all dimethylbenz(A)anthracene-induced mammary tumors examined. Transfection studies with OKL38 cDNA with MCF-7 cells resulted in growth inhibition in vitro and reduction in tumor formation in vivo. These observations led to speculation that OKL38 may play a vital role in the growth regulation and differentiation of breast epithelial cells during pregnancy and its implications in tumorigenesis.
    Endocrinology 09/2001; 142(8):3607-15. · 4.50 Impact Factor
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    T W Chan · M Pollak · H Huynh ·
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    ABSTRACT: The antiestrogens ICI 182,780 (ICI) and tamoxifen are clinically useful in the treatment of estrogen receptor-positive breast tumors. We assessed the in vivo effects of ICI, tamoxifen, and estradiol on the insulin-like growth factor (IGF) signaling pathway in the rat mammary gland. ICI significantly decreased the size of the lobular structures, Ki-67 labeling index, and insulin-like growth factor binding protein (IGFBP)-2 and IGFBP-5 gene expression. Treatment of rats with 1, 1.5, and 2 mg of ICI/kg body weight/week resulted in a 2-, 7-, and 8-fold increase in IGFBP-3 transcripts. High doses of ICI increased mammary IGF-1 gene expression by 2-fold (P < 0.01) but decreased IGF-1R and its autophosphorylation to approximately 30% of the control mammary gland. IRS-1, IRS-2, and c-Raf-1 levels in the ICI-treated mammary glands were approximately 30, 15, and 40% of controls, respectively. Basal phosphorylation of IRS-1, Akt-1, and the p85 subunit of phosphatidylinositol 3-kinase (PI-3K) were low but detectable after ICI treatment. Despite a significant reduction in levels of IGF-1R, IRS-1, and IRS-2 phosphorylation, phospho p42/p44 MAPK levels were only slightly decreased. Tamoxifen-induced growth inhibition was associated with slight stimulation of IGFBP-3 gene expression and reduction in IRS-2 levels. Basal phosphorylation of IGF-1R, IRS-1, and p85 subunit of PI-3K was decreased by tamoxifen. Estradiol-induced epithelial cell proliferation was associated with inhibition of IGFBP-3 gene expression, stimulation of IGFBP-2 gene expression, and increases in IGF-1R, IRS-1, IRS-2, and c-Raf-1 levels. Although basal phosphorylation of IGF-1R, IRS-1, IRS-2, Akt-1, and the p85 subunit of PI-3K was significantly increased by estradiol, basal phospho p44/42 MAPK was significantly reduced. The data indicate that in addition to their classic actions, antiestrogens have major effects on IGF signaling pathways.
    Clinical Cancer Research 08/2001; 7(8):2545-54. · 8.72 Impact Factor

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1k Citations
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  • 2005-2012
    • National Cancer Centre Singapore
      • • Department of Medical Oncology
      • • Division of Cellular and Molecular Research
  • 2003
    • Singapore General Hospital
      • Department of Plastic Surgery
      Tumasik, Singapore
  • 1994-2000
    • McGill University
      • • Division of Urology
      • • Department of Medicine
      Montréal, Quebec, Canada
  • 1994-1996
    • Lady Davis Institute for Medical Research
      Montréal, Quebec, Canada