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WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells.

Zhang H, Zhang YK, Wang YJ, Kathawala RJ, Patel A, Zhu H, Sodani K, Talele TT, Ambudkar SV, Chen ZS, Fu LW - Cancer Sci. (2014)

Bottom Line: We found that WHI-P154 significantly enhanced the sensitivity of ABCG2-overexpressing cells to its substrates.WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance.Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA.

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Effect of WHI-P154 on the accumulation and efflux of [3H]-MX. The accumulation of [3H]-MX was determined in both wild-type and mutant ABCG2-overexpressing ABCG2-482-R2 and ABCG2-482-G2 cells with or without WHI-P154. Columns are the mean of triplicate determinations; bars represent SD (a). *P < 0.05, **P < 0.01 versus the control group. The effects of WHI-P154 on the efflux of [3H]-MX from HEK293/pcDNA3.1 and ABCG2-482-R2 cells were measured as described in the “Materials and Methods” section (b). Data shown are means ± SD for independent determinations in triplicate.
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fig02: Effect of WHI-P154 on the accumulation and efflux of [3H]-MX. The accumulation of [3H]-MX was determined in both wild-type and mutant ABCG2-overexpressing ABCG2-482-R2 and ABCG2-482-G2 cells with or without WHI-P154. Columns are the mean of triplicate determinations; bars represent SD (a). *P < 0.05, **P < 0.01 versus the control group. The effects of WHI-P154 on the efflux of [3H]-MX from HEK293/pcDNA3.1 and ABCG2-482-R2 cells were measured as described in the “Materials and Methods” section (b). Data shown are means ± SD for independent determinations in triplicate.

Mentions: To investigate the potential reversal mechanism of ABCG2-mediated MDR by WHI-P154, we determined the effect of WHI-P154 on the accumulation of [3H]-MX in ABCG2-overexpressing cells. The intracellular level of [3H]-MX was measured in the presence or absence of WHI-P154 in ABCG2-482-R2 and ABCG2-482-G2 cells. The intracellular accumulation of [3H]-MX was lower in the drug resistant cells than that in the parental HEK293/pcDNA3.1 cells. In the presence of WHI-P154 (1 and 4 μM) and FTC (2.5 μM), the intracellular level of [3H]-MX was significantly increased in ABCG2-overexpressing cells (Fig. 2a). However, neither WHI-P154 nor FTC increased the accumulation of [3H]-MX in HEK293/pcDNA3.1 cells (Fig. 2a).


WHI-P154 enhances the chemotherapeutic effect of anticancer agents in ABCG2-overexpressing cells.

Zhang H, Zhang YK, Wang YJ, Kathawala RJ, Patel A, Zhu H, Sodani K, Talele TT, Ambudkar SV, Chen ZS, Fu LW - Cancer Sci. (2014)

Effect of WHI-P154 on the accumulation and efflux of [3H]-MX. The accumulation of [3H]-MX was determined in both wild-type and mutant ABCG2-overexpressing ABCG2-482-R2 and ABCG2-482-G2 cells with or without WHI-P154. Columns are the mean of triplicate determinations; bars represent SD (a). *P < 0.05, **P < 0.01 versus the control group. The effects of WHI-P154 on the efflux of [3H]-MX from HEK293/pcDNA3.1 and ABCG2-482-R2 cells were measured as described in the “Materials and Methods” section (b). Data shown are means ± SD for independent determinations in triplicate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317847&req=5

fig02: Effect of WHI-P154 on the accumulation and efflux of [3H]-MX. The accumulation of [3H]-MX was determined in both wild-type and mutant ABCG2-overexpressing ABCG2-482-R2 and ABCG2-482-G2 cells with or without WHI-P154. Columns are the mean of triplicate determinations; bars represent SD (a). *P < 0.05, **P < 0.01 versus the control group. The effects of WHI-P154 on the efflux of [3H]-MX from HEK293/pcDNA3.1 and ABCG2-482-R2 cells were measured as described in the “Materials and Methods” section (b). Data shown are means ± SD for independent determinations in triplicate.
Mentions: To investigate the potential reversal mechanism of ABCG2-mediated MDR by WHI-P154, we determined the effect of WHI-P154 on the accumulation of [3H]-MX in ABCG2-overexpressing cells. The intracellular level of [3H]-MX was measured in the presence or absence of WHI-P154 in ABCG2-482-R2 and ABCG2-482-G2 cells. The intracellular accumulation of [3H]-MX was lower in the drug resistant cells than that in the parental HEK293/pcDNA3.1 cells. In the presence of WHI-P154 (1 and 4 μM) and FTC (2.5 μM), the intracellular level of [3H]-MX was significantly increased in ABCG2-overexpressing cells (Fig. 2a). However, neither WHI-P154 nor FTC increased the accumulation of [3H]-MX in HEK293/pcDNA3.1 cells (Fig. 2a).

Bottom Line: We found that WHI-P154 significantly enhanced the sensitivity of ABCG2-overexpressing cells to its substrates.WHI-P154 moderately sensitized ABCB1-overexpressing KB-C2 cells to its substrates whereas showed no sensitizing effect on ABCC1-, ABCC2 or ABCC10-mediated drug resistance.Collectively, these findings highlighted WHI-P154 could significantly reverse ABCG2-mediated multidrug drug resistance by directly blocking the efflux function.

View Article: PubMed Central - PubMed

Affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St John's University, Queens, New York, USA.

Show MeSH
Related in: MedlinePlus