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Ke-Jun Liu,
Jie-Hua He, Xiao-Dong Su,
Hong-May Sim,
Jing-Dun Xie,
Xing-Gui Chen,
Fang Wang,
Yong-Ju Liang,
Satyakam Singh,
Kamlesh Sodani,
Tanaji T Talele,
Suresh V Ambudkar,
Zhe-Sheng Chen,
Hai-Ying Wu,
Li-Wu Fu
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ABSTRACT: Saracatinib, a highly selective, dual Src/Abl kinase inhibitor, is currently in a Phase II clinical trial for the treatment of ovarian cancer. In our study, we investigated the effect of saracatinib on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters in vitro and in vivo. Our results showed that saracatinib significantly enhanced the cytotoxicity of ABCB1 substrate drugs in ABCB1 overexpressing HeLa/v200, MCF-7/adr and HEK293/ABCB1 cells, an effect that was stronger than that of gefitinib, whereas it had no effect on the cytotoxicity of the substrates in ABCC1 overexpressing HL-60/adr cells and its parental sensitive cells. Additionally, saracatinib significantly increased the doxorubicin (Dox) and Rho 123 accumulation in HeLa/v200 and MCF-7/adr cells, whereas it had no effect on HeLa and MCF-7 cells. Furthermore, saracatinib stimulated the ATPase activity and inhibited photolabeling of ABCB1 with [(125) I]-iodoarylazidoprazosin in a concentration-dependent manner. In addition, the homology modeling predicted the binding conformation of saracatinib within the large hydrophobic drug-binding cavity of human ABCB1. However, neither the expression level of ABCB1 nor the phosphorylation level of Akt was altered at the reversal concentrations of saracatinib. Importantly, saracatinib significantly enhanced the effect of paclitaxel against ABCB1-overexpressing HeLa/v200 cancer cell xenografts in nude mice. In conclusion, saracatinib reverses ABCB1-mediated MDR in vitro and in vivo by directly inhibiting ABCB1 transport function, without altering ABCB1 expression or AKT phosphorylation. These findings may be helpful to attenuate the effect of MDR by combining saracatinib with other chemotherapeutic drugs in the clinic. What's new? The overexpression of ATP-binding cassette (ABC) transporters is a common reason for multidrug resistance (MDR) in cancer cells. In this study, saracatinib, a dual Src/Abl tyrosine kinase inhibitor, reversed multidrug resistance mediated by the transporter ABCB1, both in vitro and in vivo. The data indicate that saracatinib, as monotherapy or combination therapy, may be effective in overcoming ABCB1-mediated drug resistance in the clinic.
International Journal of Cancer 05/2012; · 5.44 Impact Factor
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ABSTRACT: S1-M1-80 cells, derived from human colon carcinoma S1 cells, are mitoxantrone-selected ABCG2-overexpressing cells and are widely used in in vitro studies of multidrug resistance(MDR). In this study, S1-M1-80 cell xenografts were established to investigate whether the MDR phenotype and cell biological properties were maintained in vivo. Our results showed that the proliferation, cell cycle, and ABCG2 expression level in S1-M1-80 cells were similar to those in cells isolated from S1-M1-80 cell xenografts (named xS1-M1-80 cells). Consistently, xS1-M1-80 cells exhibited high levels of resistance to ABCG2 substrates such as mitoxantrone and topotecan, but remained sensitive to the non-ABCG2 substrate cisplatin. Furthermore, the specific ABCG2 inhibitor Ko143 potently sensitized xS1-M1-80 cells to mitoxantrone and topotecan. These results suggest that S1-M1-80 cell xenografts in nude mice retain their original cytological characteristics at 9 weeks. Thus, this model could serve as a good system for further investigation of ABCG2-mediated MDR.
Chinese journal of cancer 03/2012; 31(3):150-8.
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ABSTRACT: The overexpression of ATP-binding cassette (ABC) transporters is one of the main causes of multi-drug resistance (MDR) which represents a major obstacle to the success of cancer chemotherapy. In this study, we examined the effect of BIBF 1120, an inhibitor of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs) tyrosine kinases, on the reversal of multidrug resistance in vitro.
The doxorubicin and rhodamine 123 retention assay was performed by flowcytometry. Western blot were employed to identify ABCB1 expression level and the effect of BIBF 1120 on the blockade of Akt and ERK1/2 phosphorylation. The expression of mdr1 mRNA was determined by RT-PCR analysis. The ATPase activity of ABCB1 was investigated using Pgp-Glo™ assay systems.
BIBF 1120 significantly enhanced the cytotoxicity of doxorubicin and paclitaxel and increased the accumulation of ABCB1 substrates in ABCB1-overexpressing cancer cells, whereas it had no effect on the parental cells. On the other hand, BIBF 1120 did not alter the cytotoxicity of non-ABCB1 substrates and was unable to reverse ABCC1 or ABCG2-mediated MDR. Furthermore, BIBF 1120 inhibited the ATPase activity of ABCB1 in a concentration-dependent manner. However, no detectable alteration on the expression level of mdr1 mRNA or ABCB1 protein was identified in ABCB1-overexpressing cancer cells by different treatments of BIBF 1120. Interestly, total and phosphorylated forms of AKT and ERK1/2 were not inhibited by BIBF 1120 at the reversal concentrations.
Our results suggest that BIBF 1120 is capable of overcoming ABCB1-mediated drug resistance by inhibiting ABCB1 function, which may have clinical significance for BIBF 1120 combinational treatment of certain resistant cancers.
Cellular oncology (Dordrecht). 01/2011; 34(1):33-44.
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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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Chun-ling Dai,
Yong-ju Liang,
Li-ming Chen,
Xu Zhang,
Wen-jing Deng, Xiao-dong Su,
Zhi Shi,
Chung-pu Wu,
Charles R Ashby,
Shin-ichi Akiyama,
Suresh V Ambudkar,
Zhe-sheng Chen,
Li-wu Fu
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ABSTRACT: The effectiveness of chemotherapeutic treatment is usually limited by the overexpression of adenosine triphosphate binding cassette (ABC) transporters, which mediate multidrug resistance (MDR) by acting as efflux pumps to remove chemotherapeutic agents from MDR cancer cells. Thus, the inhibition of ABC transporters may represent a promising strategy to reverse MDR. This study was to characterize the actions of FG020326, a newly synthesized triaryl-substituted imidazole derivative, to reverse MDR in vitro and in vivo. FG020326 significantly potentiated the cytotoxicity of paclitaxel, doxorubicin, and vincristine in the ABCB1 (P-glycoprotein, P-gp) overexpressing cells KBv200 and MCF-7/adr, but not in the ABCB1 negative parental cell lines KB and MCF-7. However, FG020326 did not alter the cytotoxicity of the aforementioned drugs in ABCC1 (MRP1), ABCC4 (MRP4), ABCG2 (BCRP) and LRP overexpressing cell lines, KB-CV60, NIH3T3/MRP4-2, S1-M1-80 and SW1573/2R120, respectively. FG020326, following p.o. administration, was present in concentrations sufficient for reversal of MDR in mice. The co-administration of FG020326 with paclitaxel or vincristine significantly enhanced the antitumor activity of these drugs without significantly increasing toxicity in the mice bearing the KBv200 cell xenografts. In addition, FG020326, at concentrations that reversed MDR, did not significantly affect the activity of CYP3A4 or alter the pharmacokinetic profile of paclitaxel after co-administration with paclitaxel. FG020326 produced a significant concentration-dependent displacement of [3H]azidopine and inhibition of efflux of drug from cells. Furthermore, FG020326 was co-localized with ABCB1 in cell membranes. Hence, FG020326 is characterized as a third generation MDR modulator that holds great promise for the treatment of cancer patients with ABCB1-mediated MDR.
Biochemical pharmacology 06/2009; 78(4):355-64. · 4.25 Impact Factor
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Chun-ling Dai,
Amit K Tiwari,
Chung-Pu Wu, Xiao-Dong Su,
Si-Rong Wang,
Dong-geng Liu,
Charles R Ashby,
Yan Huang,
Robert W Robey,
Yong-ju Liang,
Li-ming Chen,
Cheng-Jun Shi,
Suresh V Ambudkar,
Zhe-Sheng Chen,
Li-wu Fu
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ABSTRACT: Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (Her-1 or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2) transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters, although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1- or ABCG2-overexpressing cells and inhibited the transport of methotrexate and E(2)17betaG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic.
Cancer Research 11/2008; 68(19):7905-14. · 7.86 Impact Factor
