Kenneth K W To

The Chinese University of Hong Kong, Hong Kong, Hong Kong

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Publications (43)174.07 Total impact

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    ABSTRACT: Multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters through efflux of antineoplastic agents from cancer cells is a major obstacle to successful cancer chemotherapy. The inhibition of these ABC transporters is thus a logical approach to circumvent MDR. There has been intensive research effort to design and develop novel inhibitors for the ABC transporters to achieve this goal. In the present study, we evaluated the ability of UMMS-4 to modulate P-glycoprotein (P-gp/ABCB1)-, breast cancer resistance protein (BCRP/ABCG2)- and multidrug resistance protein (MRP1/ABCC1)-mediated MDR in cancer cells. Our findings showed that UMMS-4, at non-cytotoxic concentrations, apparently circumvents resistance to ABCB1 substrate anticancer drugs in ABCB1-overexpressing cells. When used at a concentration of 20 μmol/L, UMMS-4 produced a 17.53-fold reversal of MDR, but showed no effect on the sensitivity of drug-sensitive parental cells. UMMS-4, however, did not significantly alter the sensitivity of non-ABCB1 substrates in all cells and was unable to reverse ABCG2- and ABCC1-mediated MDR. Additionally, UMMS-4 profoundly inhibited the transport of rhodamine 123 (Rho 123) and doxorubicin (Dox) by the ABCB1 transporter. Furthermore, UMMS-4 did not alter the expression of ABCB1 at the mRNA and protein levels. In addition, the results of ATPase assays showed that UMMS-4 stimulated the ATPase activity of ABCB1. Taken together, we conclude that UMMS-4 antagonizes ABCB1-mediated MDR in cancer cells through direct inhibition of the drug efflux function of ABCB1. These findings may be useful for the development of safer and more effective MDR modulator.
    American Journal of Cancer Research 01/2014; 4(2):148-60. · 2.65 Impact Factor
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    ABSTRACT: Equol is produced by the intestinal bacteria from isoflavone daidzein. Studies have reported the health benefits of soy can only present or more pronounced in equol producers. This 6-month randomized controlled trial examined the effect of whole soy (soy flour) and purified daidzein on cardiovascular biomarkers and carotid intima-media thickness (CIMT) in prehypertensive postmenopausal women who were equol producers. Two hundred seventy eligible women were randomized to either one of the three treatments: 40 g soy flour (whole soy group), 40 g low-fat milk powder + 63 mg daidzein (daidzein group), or 40 g low-fat milk powder (placebo group) daily each for 6 months. Fasting venous samples were obtained at baseline and end of trial for testing glucose, lipids, high sensitivity C-reactive protein (hs-CRP), and free fatty acid. Changes in common CIMT were also assessed. Serum LDL-C decreased by 7.95% (95% CI: -15.09∼-0.81%) and 6.32% (95% CI: -13.45∼0.08%), and serum hs-CRP decreased by 0.164 (95% CI: -0.309∼-0.019) and 0.054 (95% CI: -0.199∼0.012) in the whole soy group compared with daidzein and milk placebo groups, respectively. No significant change in CIMT was found. Whole soy, but not purified daidzein, had a beneficial effect on reduction of LDL-C and hs-CRP among prehypertensive equol-producing postmenopausal women.
    Molecular Nutrition & Food Research 11/2013; · 4.31 Impact Factor
  • Kenneth K W To, Brian Tomlinson
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    ABSTRACT: Multidrug resistance (MDR), usually mediated by overexpression of efflux transporters such as P-gp, ABCG2 and/or MRP1, remains a major obstacle hindering successful cancer chemotherapy. There has been great interest in the development of inhibitors towards these transporters to circumvent resistance. However, since the inhibition of transporter is not specific to cancer cells, a decrease in the cytotoxic drug dosing may be needed to prevent excess toxicity, thus undermining the potential benefit brought about by a drug efflux inhibitor. The design of potent MDR modulators specific towards resistant cancer cells and devoid of drug-drug interactions will be needed to effect MDR reversal. Recent evidence suggests that the PTEN/PI3K/Akt pathway may be exploited to alter ABCG2 subcellular localization, thereby circumventing MDR. Three PPARγ agonists (telmisartan, pioglitazone and rosiglitazone) that have been used in the clinics were tested for their effect on the PTEN/PI3K/Akt pathway and possible reversal of ABCG2-mediated drug resistance. The PPARγ agonists were found to be weak ABCG2 inhibitors by drug efflux assay. They were also shown to elevate the reduced PTEN expression in a resistant and ABCG2-overexpressing cell model, which inhibit the PI3K-Akt pathway and lead to the relocalization of ABCG2 from the plasma membrane to the cytoplasma, thus apparently circumventing the ABCG2-mediated MDR. Since this PPARγ/PTEN/PI3K/Akt pathway regulating ABCG2 is only functional in drug-resistant cancer cells with PTEN loss, the PPARγ agonists identified may represent promising agents targeting resistant cells for MDR reversal.
    British Journal of Pharmacology 08/2013; · 5.07 Impact Factor
  • Kenneth K W To, S X Ren, C C M Wong, Chi Hin Cho
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    ABSTRACT: Multidrug resistance (MDR) of cancer cells to a wide spectrum of anticancer drugs is a major obstacle to successful chemotherapy. It is usually mediated by the overexpression of one of the three major ABC transporters actively pumping cytotoxic drugs out of the cells. There has been great interest in the search for inhibitors towards these transporters with an aim to circumvent resistance. This is usually achieved by screening from natural product library and the subsequent structural modifications. This study reported the reversal of ABCG2-mediated MDR in drug-selected resistant cancer cell lines by a class of host defense antimicrobial peptides, the human cathelicidin LL37 and its fragments. The effective human cathelicidin peptides (LL17-32 and LL13-37) were found to increase the accumulation of mitoxantrone in cancer cell lines with ABCG2 overexpression, thereby circumventing resistance to mitoxantrone. At the effective concentrations of the cathelicidin peptides, cell proliferation of the parental cells without elevated ABCG2 expression was not affected. Result from drug efflux and ATPase assays suggested that both LL17-32 and LL13-37 interact with ABCG2 and inhibit its transport activity in an uncompetitive manner. The peptides were also found to downregulate ABCG2 protein expression in the resistant cells, probably through a lysosomal degradation pathway. Our data suggest that the human cathelicidin may be further developed for sensitizing resistant cancer cells to chemotherapy.
    Peptides 12/2012; · 2.52 Impact Factor
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    ABSTRACT: The stromal cell-derived factor-1α SDF-1α (CXCL12)/CXCR4 axis has been linked to poor prognosis in some cancers. As histone deacetylase inhibitors (HDIs) exert antitumor effects by targeting proteins affecting cell migration, we sought to evaluate the effects of the HDIs apicidin, vorinostat, entinostat (MS-275) and romidepsin on the expression and function of CXCR4 in human cancer cell lines. After treatment with romidepsin, CXCR4 mRNA expression increased 12-fold in UOK121 renal cancer cells, 16-fold in H460 non-small cell cancer cells and 4-fold in SF295 glioma cells; treatment with other HDIs yielded similar effects. CXCR4 induction was not observed in MCF7 breast cancer cells or SW620 colon cancer cells. To evaluate the corresponding functional increase, the effect of CXCR4 ligand, CXCL12, on ERK1/2, STAT3 and c-SRC activation and cell migration was examined in UOK121, SF295 and H460 cells. Alone, the HDIs increased pERK1/2, while reducing pSTAT-3 and pSRC. Following CXCL12 exposure, pERK1/2 induction was maintained, but STAT3 and SRC phosphorylation was impaired. These findings resulted in reduced basal and CXCL12-mediated cell migration. In conclusion, HDIs upregulated CXCR4 mRNA expression but impaired CXCL12-dependent signaling cascades through STAT3 and c-SRC, suggesting a potential role for HDIs in delaying or preventing metastatic processes in solid tumors.
    Cancer biology & therapy 11/2012; 14(2). · 3.29 Impact Factor
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    ABSTRACT: Development of antiandrogen-resistance in advanced prostate cancer involves multiple androgen receptor (AR)-dependent and -independent pathways. Here, we demonstrated that endothelial nitric oxide synthase (eNOS) exhibited an overexpression pattern in hormone-refractory prostate cancer and several models of advanced hormone-resistant prostate cancer. We further established a novel in vitro model of antiandrogen-resistant prostate cancer (LNCaP-BC) by long-term bicalutamide treatment. Besides antiandrogen-resistant and other enhanced malignant growth phenotypes, LNCaP-BC cells exhibited an increased activated eNOS expression and NO production, and suppressed AR transactivation status. Treatment with a NOS inhibitor L-NAME could re-sensitize the growth response to bicalutamide and enhance the AR transactivation in LNCaP-BC cells. Together, our present findings indicate that increased NO production by acquired increased expression of activated eNOS could contribute to the antiandrogen-resistant growth of prostate cancer cells, via a mechanism of NO-mediated suppression of AR activity, and also targeting eNOS could be a potential therapeutic strategy for antiandrogen-resistant prostate cancer.
    Cancer letters 09/2012; · 4.86 Impact Factor
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    ABSTRACT: Low selectivity is one of the major problems of currently used anticancer drugs, therefore, there is a high demand for novel, selective antitumor agents. In this study, the anticancer effects and mechanisms of guttiferone K (GUTK), a novel polyprenylated acylphloroglucinol derivative isolated from Garcinia cowa Roxb., were examined for its development as a novel drug targeting colon cancer. GUTK concentration- and time-dependently reduced the viability of human colon cancer HT-29 cells (IC(50) value 5.39 ± 0.22 μM) without affecting the viability of normal human colon epithelial CCD 841 CoN cells and induced G(0) /G(1) cell cycle arrest in HT-29 cells by down-regulating cyclins D1, D3 and cyclin-dependent kinases 4 and 6, while selectively restoring p21Waf1/Cip1 and p27Kip1 to levels comparable to those observed in normal colon cells, without affecting their levels in normal cells. GUTK (10.0 μM) induced cleavage of PARP, caspases-3, -8 and -9 and chromatin condensation to stimulate caspase-3-mediated apoptosis. The addition of a JNK inhibitor, SP600125, partially reversed GUTK-induced caspase-3 activity, indicating the possible involvement of JNK in GUTK-induced apoptosis. Furthermore, GUTK (10 mg/kg, i.p.) significantly decreased the tumor volume in a syngeneic colon tumor model when used alone or in combination with 5-fluorouracil without toxicity to the mice. Immunohistochemical staining of the tumor sections revealed a mechanism involving an increase in cleaved caspase-3 and a decrease in cell proliferation marker Ki-67. Our results support GUTK as a promising novel, potent and selective antitumor drug candidate for colon cancer.
    International Journal of Cancer 06/2012; · 6.20 Impact Factor
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    ABSTRACT: Stemlike cells have been isolated by their ability to efflux Hoechst 33342 dye and are called the side population (SP). We evaluated the effect of axitinib on targeting cancer stemlike cells and enhancing the efficacy of chemotherapeutical agents. We found that axitinib enhanced the cytotoxicity of topotecan and mitoxantrone in SP cells sorted from human lung cancer A549 cells and increased cell apoptosis induced by chemotherapeutical agents. Moreover, axitinib particularly inhibited the function of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) and reversed ABCG2-mediated multidrug resistance (MDR) in vitro. However, no significant reversal effect was observed in ABCB1-, ABCC1- or lung resistance-related protein (LRP)-mediated MDR. Furthermore, in both sensitive and MDR cancer cells axitinib neither altered the expression of ABCG2 at the mRNA or protein levels nor blocked the phosphorylation of AKT and extracellular signal-regulated kinase (ERK)1/2. In nude mice bearing ABCG2-overexpressing S1-M1-80 xenografts, axitinib significantly enhanced the antitumor activity of topotecan without causing additional toxicity. Taken together, these data suggest that axitinib particularly targets cancer stemlike cells and reverses ABCG2-mediated drug resistance by inhibiting the transporter activity of ABCG2.
    Molecular Medicine 04/2012; 18(1):887-98. · 4.47 Impact Factor
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    ABSTRACT: The lack of selectivity and adequate potency of currently known P-glycoprotein (P-gp) inhibitors obscured their further development for clinical use to circumvent P-gp-mediated multidrug resistance (MDR), which necessitates the investigation of novel ones with higher potency and better specificity. The present study investigated the reversal effect of a new synthetic α-aminoxy lysine-peptidomimetic (Lys-P) on P-gp-mediated MDR. Effects of Lys-P on cytotoxicity of P-gp substrate doxorubicin (Dox) and intracellular accumulation of another P-gp substrate rhodamine 123 were examined in HEK293 cells. Its interaction mechanism and effect on P-gp expression were further investigated using ATPase assay and Western blot in Caco-2 cells, respectively. Lys-P restored the cytotoxicity of Dox toward the resistant MDR1-transfected HEK293 and MCF-7 TX400 cells without affecting their corresponding parental cells. It also significantly increased intracellular accumulation (21-fold) of rhodamine 123 in HEK293 MDR1 cells. Further mechanistic studies demonstrated that in the Caco-2 cell monolayer model, Lys-P abolished the P-gp-mediated efflux of Dox due to uncompetitive inhibition of P-gp ATPase without altering P-gp expression. Our findings demonstrated that Lys-P can be used as a promising lead compound for further development into selective and efficient MDR reversing agents for combination use with P-gp substrate drugs in cancer chemotherapy.
    International journal of pharmaceutics 03/2012; 424(1-2):33-9. · 2.96 Impact Factor
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    ABSTRACT: Besides targeting the well-known oncogenic c-Met, crizotinib is the first oral tyrosine kinase inhibitor inhibiting anaplastic lymphoma kinase (ALK) in clinical trials for the treatment of non-small cell lung cancer. Here, we assessed the possible reversal of multidrug resistance (MDR) by crizotinib in vitro and in vivo. 1-(4,5-Dimethylthiazol-2-yl)-3,5- diphenylformazan was used in vitro and xenografts in nude mice were used in vivo to investigate reversal of MDR by crizotinib. To understand the mechanisms for MDR reversal, the alterations of intracellular doxorubicin or rhodamine 123 accumulation, doxorubicin efflux, ABCB1 expression level, ATPase activity of ABCB1 and crizotinib-induced c-Met, Akt and ERK1/2 phosphorylation were examined. Crizotinib significantly enhanced the cytotoxicity of chemotherapeutic agents which are also ABCB1 substrates, in MDR cells with no effect found on sensitive cells in vitro and in vivo. Additionally, crizotinib significantly increased intracellular accumulation of rhodamine 123 and doxorubicin and inhibited the drug efflux in ABCB1-overexpressing MDR cells. Further studies showed that crizotinib enhanced the ATPase activity of ABCB1 in a concentration-dependent manner. However, expression of ABCB1 was not affected, and reversal of MDR by crizotinib was not related to the phosphorylation of c-Met, Akt or ERK1/2. Importantly, crizotinib significantly enhanced the effect of paclitaxel against KBv200 cell xenografts in nude mice. Crizotinib reversed ABCB1-mediated MDR by inhibiting ABCB1 transport function without affecting ABCB1 expression or blocking the Akt or ERK1/2 pathways. These findings are useful for planning combination chemotherapy of crizotinib with conventional chemotherapeutic drugs.
    British Journal of Pharmacology 01/2012; 166(5):1669-83. · 5.07 Impact Factor
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    Grace M Y Cheng, Kenneth K W To
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    ABSTRACT: ABCG2 is an efflux transporter commonly found to overexpress in multidrug resistant (MDR) cancer cells. It is also believed to be a survival factor for cancer stem cells to drive tumor growth. Tumor microenvironment represents an attractive new drug target because it allows complex interaction between a tumor and its surrounding normal cells, molecules, and blood vessels, which all participate in tumor progression. Hypoxia, glucose deprivation and acidosis are the hallmarks of tumor microenvironment. This study investigated the upregulation of ABCG2 by these adverse growth conditions within the tumor microenvironment. Reporter gene assay revealed that a region within the ABCG2 promoter close to the reported HIF-1α response element is responsible for ABCG2 upregulation. Increased ABCG2 efflux activity was observed under the same conditions, subsequently leading to reduced response to ABCG2 substrate anticancer drug. Importantly, glucose deprivation and hypoxia were also found to enhance the resistance level of ABCG2-overexpressing resistant cells with pre-existing genetic and epigenetic MDR mechanisms. Hypoxia was further demonstrated to cause a more malignant anchorage-independent growth phenotype in the resistant cells, which can be abolished by knocking down ABCG2. A better understanding of ABCG2 regulation by the tumor microenvironment may help design novel strategies to improve treatment outcome.
    ISRN oncology. 01/2012; 2012:746025.
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    ABSTRACT: P-glycoprotein (P-gp, ABCB1) overexpression and enrichment of stem-like cells are linked to poor prognosis in tumor patients. In this study, we investigated the effect of apatinib, an oral multi-targeted tyrosine kinase inhibitor (TKI) on enhancing the efficacy of conventional anticancer drugs in side population (SP) cells and ABCB1-overexpressing leukemia cells in vitro, in vivo and ex vivo. Our results showed that apatinib significantly enhanced the cytotoxicity and cell apoptosis induced by doxorubicin in SP cells sorted from K562 cells. Furthermore, apatinib also strongly reversed multidrug resistance (MDR) in K562/ADR cells, and the primary leukemia blasts overexpressing ABCB1 while showed no synergistic interactions with chemotherapeutic agents in MRP1-, MRP4-, MRP7- and LRP-overexpressing cells. Apatinib treatment markedly increased the intracellular accumulation of doxorubicin and rhodamine 123 in K562/ADR cells and the accumulation of rhodamine 123 in the primary leukemia blasts with ABCB1 overexpression. Apatinib stimulated the ATPase activity of P-gp in a dose-dependent manner but did not alter the expression of ABCB1 at both mRNA and protein levels. The phosphorylation level of AKT and ERK1/2 remained unchanged after apatinib treatment in both sensitive and MDR cells. Importantly, apatinib significantly enhanced the antitumor activity of doxorubicin in nude mice bearing K562/ADR xenografts. Taken together, our results suggest that apatinib could target to SP cells and ABCB1-overexpressing leukemia cells to enhance the efficacy of chemotherapeutic drugs. These findings should be useful for the combination of apatinib and chemotherapeutic agents in the clinic.
    Biochemical pharmacology 12/2011; 83(5):586-97. · 4.25 Impact Factor
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    10/2011; , ISBN: 978-953-307-612-6
  • Kenneth K W To, Le Yu, Shuwen Liu, Jianhua Fu, Chi Hin Cho
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    ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is a highly malignant disease that is generally not responding to chemotherapy. It is particularly predominant in China. Although ESCC is significantly associated with cigarette smoking, the relationship between its molecular pathogenesis and responsiveness to chemotherapy and cigarette smoke remains elusive. This study reported the constitutive activation of aryl hydrocarbon receptor (AhR), leading to ABCG2 upregulation and the multidrug resistance (MDR) phenotype, in ESCC cell lines with acquired cisplatin resistance. Reporter gene assay, chromatin immunoprecipitation analysis and specific gene knockdown confirmed that the enhanced AhR binding to a xenobiotic response element (XRE) within the ABCG2 promoter is responsible for ABCG2 overexpression. A HSP90 inhibitor (17-AAG) and two AhR antagonists (kaempferol and salicylamide) were shown to inhibit ABCG2 upregulation, thereby reversing the ABCG2-mediated MDR. Our data therefore advocate the use of these inhibitors as novel chemosensitizers for the treatment of esophageal cancer.
    Molecular Carcinogenesis 06/2011; 51(6):449-64. · 4.27 Impact Factor
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    ABSTRACT: Functional polymorphisms of the ABCG2 gene may contribute to individual variability in drug response and the prognosis of patients. In the present study, the genetic polymorphisms and expression of ABCG2 were analysed in blasts cells obtained from 184 Chinese patients with de novo acute leukaemia to investigate their possible association with clinical outcomes. A novel synonymous ABCG2-single nucleotide polymorphism (SNP) at exon 16 (13561218 C/T) and five known SNPs at exon 2 (13608835 G/A), exon 5 (13600044 C/A), intron 10 (13576005 C/T), intron 13 (13564503 C/T) and intron 14 (13563578 A/G) were identified with occurrence rates of 1.1%, 64.1%, 30.4%, 21.2%, 39.7% and 28.8%, respectively. We found that patients with the ABCG2 34GG genotype displayed longer disease free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001) than those with the 34GA/AA genotypes. Furthermore, the DFS and OS were significantly diminished in bone marrow transplantation (BMT) patients with the 34GA/AA genotypes relative to those with the 34GG genotype. These results suggest that these highly prevalent ABCG2 34GA/AA genotypes are associated with poor prognosis of Chinese patients with acute leukaemia and BMT patients.
    European journal of cancer (Oxford, England: 1990) 04/2011; 47(13):1990-9. · 4.12 Impact Factor
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    ABSTRACT: Histone deacetylase inhibitors (HDACI) are promising anticancer agents and their use in combination with conventional anticancer drugs is currently under investigation. We previously reported cell line-specific upregulation of ABCG2, a multidrug resistance transporter shown to control oral bioavailability and CNS penetration, by the HDACI romidepsin, although the precise mechanism in a particular cell line remains to be determined. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by numerous environmental contaminants and has been shown to be a client protein of heat shock protein 90 (Hsp90). A xenobiotic response element was defined in the ABCG2 promoter and was shown to mediate AhR signaling. Activated AhR was found to be associated with the ABCG2 promoter only in cell line models that respond to romidepsin with ABCG2 upregulation. Our data suggest that romidepsin acetylated Hsp70 and inhibited the chaperone function of Hsp90, thereby allowing the dissociation of AhR from Hsp90. The dissociation of AhR from Hsp90 may be a prerequisite for the differential upregulation of ABCG2 by romidepsin. Increasing our understanding of the mechanism(s) governing differential upregulation of ABCG2 in response to romidepsin could provide an insight into strategies needed to tackle resistance to HDACIs in cancer therapeutics.
    Molecular Cancer Research 02/2011; 9(4):516-27. · 4.35 Impact Factor
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    ABSTRACT: The ABCG2 efflux transporter is expressed in multiple tissues and plays an important role in the disposition of many statins. The functional 421C>A polymorphism in ABCG2 that reduces transporter activity has been found to be associated with increased systemic exposures to certain statins. We review and evaluate the associations of the ABCG2 polymorphism on the pharmacokinetics and clinical efficacy of statins. This article gives a detailed overview of the ABCG2 transporter and extensively reviews its relations with the pharmacokinetics and lipid-lowering effects of statins. This review also discusses the potential role of the ABCG2 polymorphism in the clinical outcomes in statin-treated patients and statin-drug interactions. The impact of the ABCG2 421C>A polymorphism on the disposition of the statins varies between different drugs and the effect on systemic exposure was greater in the case of rosuvastatin than other statins. This genetic variant was associated with greater low-density lipoprotein cholesterol response to rosuvastatin in Chinese and caucasian patients. The effect of the ABCG2 421C>A polymorphism on the lipid response to other substrate statins and clinical outcomes need to be evaluated in future studies.
    Expert Opinion on Drug Metabolism &amp Toxicology 01/2011; 7(1):49-62. · 2.94 Impact Factor
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    ABSTRACT: We investigated the correlation between MDR1 promoter methylation status and MDR1 expression in 228 hematologic malignancies patients and 90 healthy controls. High level of MDR1 mRNA correlated to promoter hypomethylation and strongly associated with poor prognosis indicated by 2-year survival rates, poor CR rate (without BMT) and high relapse rate (with BMT). Furthermore, relative luciferase activity of methylated MDR1 at promoter -50 region was significantly higher than that of the unmethylated. In addition, MDR1 in K562 cells elevated significantly after 5-Aza-dC treatment. In summary, MDR1 promoter hypomethylation conferred its up-regulation and indicated poor prognosis in patients with and without BMT.
    Leukemia research 01/2011; 35(1):73-9. · 2.36 Impact Factor
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    ABSTRACT: Apatinib, a small-molecule multitargeted tyrosine kinase inhibitor, is in phase III clinical trial for the treatment of patients with non-small-cell lung cancer and gastric cancer in China. In this study, we determined the effect of apatinib on the interaction of specific antineoplastic compounds with P-glycoprotein (ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2). Our results showed that apatinib significantly enhanced the cytotoxicity of ABCB1 or ABCG2 substrate drugs in KBv200, MCF-7/adr, and HEK293/ABCB1 cells overexpressing ABCB1 and in S1-M1-80, MCF-7/FLV1000, and HEK293/ABCG2-R2 cells overexpressing ABCG2 (wild-type). In contrast, apatinib did not alter the cytotoxicity of specific substrates in the parental cells and cells overexpressing ABCC1. Apatinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin in the multidrug resistance (MDR) cells. Furthermore, apatinib significantly inhibited the photoaffinity labeling of both ABCB1 and ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. The ATPase activity of both ABCB1 and ABCG2 was significantly increased by apatinib. However, apatinib, at a concentration that produced a reversal of MDR, did not significantly alter the ABCB1 or ABCG2 protein or mRNA expression levels or the phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Importantly, apatinib significantly enhanced the effect of paclitaxel against the ABCB1-resistant KBv200 cancer cell xenografts in nude mice. In conclusion, apatinib reverses ABCB1- and ABCG2-mediated MDR by inhibiting their transport function, but not by blocking the AKT or ERK1/2 pathway or downregulating ABCB1 or ABCG2 expression. Apatinib may be useful in circumventing MDR to other conventional antineoplastic drugs.
    Cancer Research 09/2010; 70(20):7981-91. · 8.65 Impact Factor
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    ABSTRACT: Marine-derived fungi provide plenty of structurally unique and biologically active secondary metabolites. We screened 87 marine products from mangrove fungi in the South China Sea for anticancer activity by MTT assay. 14% of the compounds (11/86) exhibited a potent activity against cancer in vitro. Importantly, some compounds such as compounds 78 and 81 appeared to be promising for treating cancer patients with multidrug resistance, which should encourage more efforts to isolate promising candidates for further development as clinically useful chemotherapeutic drugs. Furthermore, DNA intercalation was not involved in their anticancer activities, as determined by DNA binding assay. On the other hand, the structure-activity analysis indicated that the hydroxyl group was important for their cytotoxic activity and that bulky functional groups such as phenyl rings could result in a loss of biological activity, which will direct the further development of marine product-based derivatives.
    Marine Drugs 01/2010; 8(4):1094-1105. · 3.98 Impact Factor

Publication Stats

576 Citations
174.07 Total Impact Points

Institutions

  • 2002–2013
    • The Chinese University of Hong Kong
      • Department of Pharmacy
      Hong Kong, Hong Kong
  • 2009–2012
    • Sun Yat-Sen University
      • Department of Chemical Engineering
      Guangzhou, Guangdong Sheng, China
  • 2008
    • National Cancer Institute (USA)
      • Center for Cancer Research
      Bethesda, MD, United States
  • 2004–2008
    • National Institutes of Health
      • • Center for Cancer Research
      • • Laboratory of Human Carcinogenesis
      Bethesda, MD, United States