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ABSTRACT: The side population cells characterized by the ability to transport Hoechst 33342 out of cells have been identified as cancer stem-like cells. ABCG2 is found to confer the side population (SP) phenotype, multidrug resistance (MDR) and tumor recurrence. In this study, we found secalonic acid D (SAD), a metabolite of marine-derived mangrove endophytic fungus, showed potent anticancer effect on ABCB1-, ABCC1- and ABCG2- overexpressing multidrug resistance cells by MTT assay. Furthermore, SAD could down-regulate the expression of ABCG2 and decrease the percentage of SP cells in lung cancer cells. The MTT assay showed the sorted SP cells were sensitive to SAD and we also found SAD could inhibit the sphere-forming ability of SP cells. Although SAD did not affect the expression of ABCG2 mRNA, it shortened the half-life of ABCG2 protein by activating calpain 1. These results implicated that SAD could be developed as a leading compound to target cancer stem cells and would be a promising agent to treat lung cancer patients.
Biochemical pharmacology 04/2013; · 4.25 Impact Factor
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Jian-ye Zhang,
Yan-jun Mi,
Shu-peng Chen,
Fang Wang,
Yong-ju Liang,
Li-sheng Zheng,
Cheng-jun Shi, Li-yang Tao,
Li-ming Chen,
Hu-biao Chen,
Li-wu Fu
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ABSTRACT: Euphorbia factor L1 (EFL1) belongs to diterpenoids of genus Euphorbia. In this article, its reversal activity against ABCB1-mediated MDR in KBv200 and MCF-7/adr cells was reported. However, EFL1 did not alter the sensitivity of KB and MCF-7 cells to chemotherapeutic agents. Meanwhile, EFL1 significantly increased accumulation of doxorubicin and rhodamine 123 in KBv200 and MCF-7/adr cells, showing no significant influence on that of KB and MCF-7 cells. Furthermore, EFL1 could enhance the ATP hydrolysis activity of ABCB1 stimulated by verapamil. At the same time, EFL1 inhibited the efflux of ABCB1 in KBv200 and MCF-7/adr cells. In addition, EFL1 did not downregulate expression of ABCB1 in KBv200 and MCF-7/adr cells either in mRNA or protein level.
Journal of Cellular Biochemistry 01/2011; 112(4):1076-83. · 2.87 Impact Factor
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Yan-Jun Mi,
Yong-Ju Liang,
Hong-Bing Huang,
Hong-Yun Zhao,
Chung-Pu Wu,
Fang Wang, Li-Yang Tao,
Chuan-Zhao Zhang,
Chun-Ling Dai,
Amit K Tiwari,
Xiao-Xu Ma,
Kenneth Kin Wah To,
Suresh V Ambudkar,
Zhe-Sheng Chen,
Li-Wu Fu
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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. · 7.86 Impact Factor
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Li-yang Tao,
Jian-ye Zhang,
Yong-ju Liang,
Li-ming Chen,
Li-sheng Zhen,
Fang Wang,
Yan-jun Mi,
Zhi-gang She,
Kenneth Kin Wah To,
Yong-cheng Lin,
Li-wu Fu
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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):1094-105. · 3.85 Impact Factor
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Jian-ye Zhang, Li-yang Tao,
Yong-ju Liang,
Li-ming Chen,
Yan-jun Mi,
Li-sheng Zheng,
Fang Wang,
Zhi-gang She,
Yong-cheng Lin,
Kenneth Kin Wah To,
Li-wu Fu
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ABSTRACT: In this article, we report anticancer activity of 14 anthracenedione derivatives separated from the secondary metabolites of the mangrove endophytic fungi Halorosellinia sp. (No. 1403) and Guignardia sp. (No. 4382). Some of them inhibited potently the growth of KB and KBv200 cells, among which compound 6 displayed strong cytotoxicity with IC(50) values of 3.17 and 3.21 microM to KB and KBv200 cells, respectively. Furthermore, we demonstrate that the mechanism involved in the apoptosis induced by compound 6 is probably related to mitochondrial dysfunction. Additionally, the structure-activity relationships of these compounds are discussed.
Marine Drugs 01/2010; 8(4):1469-81. · 3.85 Impact Factor
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ABSTRACT: Our previous studies have shown that tetrandrine (Tet) reverses the effect of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) both in vitro and in vivo. 5-Bromotetrandrine (Br-Tet) is a newly synthesized brominated derivative of Tet. In this study, we investigated the MDR reversal activity of Br-Tet in vitro and in vivo and the mechanism involved in this reversal.
The ability of Br-Tet to reverse drug resistance in vitro was evaluated by MTT assay in human MDR KBv200 cells and the parental drug-sensitive KB cells. A KBv200 cell xenograft model was established to investigate the MDR reversal activity of Br-Tet in vivo. Doxorubicin (Dox) accumulation in KBv200 and KB cell lines was determined by flow cytometry and Dox accumulation in KBv200 xenografts tissue was examined by spectrofluorometer. The effect of Br-Tet on the expression of P-glycoprotein was detected by flow cytometry and Western blot, respectively.
Br-Tet significantly enhanced the cytotoxicity of Dox, paclitaxel, taxotere, vincristine and epirubicin in KBv200 cells but not in KB cells. Co-administration of 10 mg/kg Br-Tet and 2 mg/kg epirubicin significantly enhanced the antitumor activity of epirubicin without increasing the toxicity. Br-Tet increased the Dox accumulation in the MDR KBv200 cell line and in KBv200 xenograft tissue in a time- and dose-dependent manner. However, it did not reduce the expression of P-gp in KBv200 cells.
Br-Tet caused a significant reversal of P-gp-mediated MDR, not only in vitro but also in vivo. The MDR reversal activity of Br-Tet in vivo was associated with the enhancement of accumulation of chemotherapeutical drugs in tumor tissue.
Anticancer research 11/2009; 29(11):4597-604. · 1.73 Impact Factor
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ABSTRACT: The anticancer activities of secalonic acid D separated from the secondary metabolites of the mangrove endophytic fungus No. ZSU44 were investigated in this study. Secalonic acid D showed potent cytotoxicity to HL60 and K562 cells, and the IC(50) values were 0.38 and 0.43 mumol/L, respectively. Annexin V-FITC/PI assay and western blot indicated that secalonic acid D induced apoptosis in HL60 and K562 cells. In addition, secalonic acid D led to cell cycle arrest of G(1) phase related to downregulation of c-Myc. Moreover, our data indicated that downregulation of c-Myc and cell cycle arrest of G(1) phase were caused not by formation of G-quadruplex structures but by activation of GSK-3beta followed by degradation of beta-catenin.
Cell cycle (Georgetown, Tex.) 09/2009; 8(15):2444-50. · 5.36 Impact Factor
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ABSTRACT: Cediranib (recentin, AZD2171) is an oral small-molecule multiple receptor tyrosine kinases inhibitor. Here we investigate the ability of cediranib to reverse tumor multidrug resistance (MDR) due to overexpression of ABCB1 (P-glycoprotein) and ABCC1 (MRP1) transporters.
KBv200,MCF-7/adr, C-A120 and their parental sensitive cell lines KB, MCF-7 and KB-3-1 were used for reversal study. The intracellular accumulations of doxorubicin and rhodamine 123 were determined by flow cytometry. The expressions levels of ABCB1 and ABCC1 were investigated by Western blot and RT-PCR analyses. ATPase activity assay were performed by Luminescence. The functions of ERK in MCF-7/adr were investigated by RNA interference.
Cediranib significantly enhanced the sensitivity of ABCB1 or ABCC1 substrates in MDR cells, with no effect found on sensitive cells. However, the expressions of these transporters were not affected and the reversal activity of cediranib was not related to the phosphorylation of AKT or ERK1/2. Further studies showed that cediranib inhibited ATPase activity of ABCB1 (P-glycoprotein) in a dose-dependent manner.
Cediranib reverses ABCB1- and ABCC1-mediated MDR by directly inhibiting their drug efflux function. These findings may be useful for cancer combinational therapy with cediranib in the clinic.
Cancer Chemotherapy and Pharmacology 04/2009; 64(5):961-9. · 2.83 Impact Factor
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Li-sheng Zheng,
Fang Wang,
Yu-hong Li,
Xu Zhang,
Li-ming Chen,
Yong-ju Liang,
Chun-ling Dai,
Yan-yan Yan, Li-yang Tao,
Yan-jun Mi,
An-kui Yang,
Kenneth Kin Wah To,
Li-wu Fu
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ABSTRACT: ABCC1 and ABCG2 are ubiquitous ATP-binding cassette transmembrane proteins that play an important role in multidrug resistance (MDR). In this study, we evaluated the possible interaction of vandetanib, an orally administered drug inhibiting multiple receptor tyrosine kinases, with ABCC1 and ABCG2 in vitro.
MDR cancer cells overexpressing ABCC1 or ABCG2 and their sensitive parental cell lines were used. MTT assay showed that vandetanib had moderate and almost equal-potent anti-proliferative activity in both sensitive parental and MDR cancer cells. Concomitant treatment of MDR cells with vandetanib and specific inhibitors of ABCC1 or ABCG2 did not alter their sensitivity to the former drug. On the other hand, clinically attainable but non-toxic doses of vandetanib were found to significantly enhance the sensitivity of MDR cancer cells to ABCC1 or ABCG2 substrate antitumor drugs. Flow cytometric analysis showed that vandetanib treatment significantly increase the intracellular accumulation of doxorubicin and rhodamine 123, substrates of ABCC1 and ABCG2 respectively, in a dose-dependent manner (P<0.05). However, no significant effect was shown in sensitive parental cell lines. Reverse transcription-PCR and Western blot analysis showed that vandetanib did not change the expression of ABCC1 and ABCG2 at both mRNA and protein levels. Furthermore, total and phosphorylated forms of AKT and ERK1/2 remained unchanged after vandetanib treatment in both sensitive and MDR cancer cells.
Vandetanib is unlikely to be a substrate of ABCC1 or ABCG2. It overcomes ABCC1- and ABCG2-mediated drug resistance by inhibiting the transporter activity, independent of the blockade of AKT and ERK1/2 signal transduction pathways.
PLoS ONE 02/2009; 4(4):e5172. · 4.09 Impact Factor
