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Curcumin Improves the Tumoricidal Effect of Mitomycin C by Suppressing ABCG2 Expression in Stem Cell-Like Breast Cancer Cells.

Zhou Q, Ye M, Lu Y, Zhang H, Chen Q, Huang S, Su S - PLoS ONE (2015)

Bottom Line: MMC or curcumin alone only marginally reduced the BCSC population in the mammospheres; however, together, they reduced the BCSC population in CD44+CD24-/low cells by more than 75% (29.34% to 6.86%).Curcumin sensitized BCSCs through a reduction in the expression of ATP-binding cassette (ABC) transporters ABCG2 and ABCC1.We demonstrated that fumitremorgin C, a selective ABCG2 inhibitor, reduced BCSC survival to a similar degree as curcumin did.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

ABSTRACT
Cancer cells with stem cell-like properties contribute to the development of resistance to chemotherapy and eventually to tumor relapses. The current study investigated the potential of curcumin to reduce breast cancer stem cell (BCSC) population for sensitizing breast cancer cells to mitomycin C (MMC) both in vitro and in vivo. Curcumin improved the sensitivity of paclitaxel, cisplatin, and doxorubicin in breast cancer cell lines MCF-7 and MDA-MB-231, as shown by the more than 2-fold decrease in the half-maximal inhibitory concentration of these chemotherapeutic agents. In addition, curcumin sensitized the BCSCs of MCF-7 and MDA-MB-231 to MMC by 5- and 15-fold, respectively. The BCSCs could not grow to the fifth generation in the presence of curcumin and MMC. MMC or curcumin alone only marginally reduced the BCSC population in the mammospheres; however, together, they reduced the BCSC population in CD44+CD24-/low cells by more than 75% (29.34% to 6.86%). Curcumin sensitized BCSCs through a reduction in the expression of ATP-binding cassette (ABC) transporters ABCG2 and ABCC1. We demonstrated that fumitremorgin C, a selective ABCG2 inhibitor, reduced BCSC survival to a similar degree as curcumin did. Curcumin sensitized breast cancer cells to chemotherapeutic drugs by reducing the BCSC population mainly through a reduction in the expression of ABCG2.

No MeSH data available.


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Effect of verapamil and curcumin on reversal of resistance to MMC in MDA-MB-231-derived BCSCs.(A) Cell survival was observed in MDA-MB-23-BCSCs and parental MDA-MB-231. Cells were treated with different concentrations for 48 h. *P < 0.05 compared with untreated control. (B) Dose- and time-dependent effect of MMC with and without verapamil and curcumin. *P < 0.05 compared with MMC and verapamil at corresponding doses. Cell survival was analyzed using MTT. Values are mean ± SD from 3 independent experiments. (C) Western blot analysis of ABCC2, ABCB1, ABCG2, and ABCC1 by curcumin and MMC with and without verapamil treatment in MDA-MB-231 BCSCs. Cells were incubated with 40 μmol/L curcumin, 25 μmol/L MMC, 10 μM/L verapamil and their combinations during 72 h. *P < 0.05 compared with MMC alone. (D) MDA-MB-231-derived BCSCs were treated with 40 μmol/L curcumin and 25 μmol/L MMC alone and together with and without fumitremorgin C and probenecid for 72 h. An MTT assay was performed. Values are mean ± SD from 3 independent experiments. *P < 0.05 compared with MMC alone.
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pone.0136694.g004: Effect of verapamil and curcumin on reversal of resistance to MMC in MDA-MB-231-derived BCSCs.(A) Cell survival was observed in MDA-MB-23-BCSCs and parental MDA-MB-231. Cells were treated with different concentrations for 48 h. *P < 0.05 compared with untreated control. (B) Dose- and time-dependent effect of MMC with and without verapamil and curcumin. *P < 0.05 compared with MMC and verapamil at corresponding doses. Cell survival was analyzed using MTT. Values are mean ± SD from 3 independent experiments. (C) Western blot analysis of ABCC2, ABCB1, ABCG2, and ABCC1 by curcumin and MMC with and without verapamil treatment in MDA-MB-231 BCSCs. Cells were incubated with 40 μmol/L curcumin, 25 μmol/L MMC, 10 μM/L verapamil and their combinations during 72 h. *P < 0.05 compared with MMC alone. (D) MDA-MB-231-derived BCSCs were treated with 40 μmol/L curcumin and 25 μmol/L MMC alone and together with and without fumitremorgin C and probenecid for 72 h. An MTT assay was performed. Values are mean ± SD from 3 independent experiments. *P < 0.05 compared with MMC alone.

Mentions: A hallmark of cancer stem cells is the enhanced ABC transporter expression that protects them from cytotoxic agent–induced damage. The observation that curcumin enhances the ability of MMC to induce BCSC cell death led to the hypothesis that curcumin modulated ABC transporter expression in BCSCs. To test this hypothesis, we first determined the IC50 of MMC in parental MDA-MB-231 cells and MDA-MB-231–derived BCSCs. An MTT viability assay showed a 6-fold increase in the IC50 of MMC in MDA-MB-231–derived BCSCs over their parental cells (Fig 4A). We subsequently examined the IC50 of MMC in MDA-MB-231–derived BCSCs with curcumin or verapamil. Verapamil reduced the IC50 of MMC from 50 to approximately 30 μmol/L, whereas curcumin reduced the IC50 to 20 μmol/L at 72 h (Fig 4B). We subsequently analyzed the effect of curcumin on ABC transporter levels in BCSCs through Western blotting; compared with untreated or MMC-treated cells, curcumin blocked 50% of ABCG2 and ABCC1 (Fig 4C). By contrast, verapamil did not significantly alter the expression of any of these ABC transporters (Fig 4C).


Curcumin Improves the Tumoricidal Effect of Mitomycin C by Suppressing ABCG2 Expression in Stem Cell-Like Breast Cancer Cells.

Zhou Q, Ye M, Lu Y, Zhang H, Chen Q, Huang S, Su S - PLoS ONE (2015)

Effect of verapamil and curcumin on reversal of resistance to MMC in MDA-MB-231-derived BCSCs.(A) Cell survival was observed in MDA-MB-23-BCSCs and parental MDA-MB-231. Cells were treated with different concentrations for 48 h. *P < 0.05 compared with untreated control. (B) Dose- and time-dependent effect of MMC with and without verapamil and curcumin. *P < 0.05 compared with MMC and verapamil at corresponding doses. Cell survival was analyzed using MTT. Values are mean ± SD from 3 independent experiments. (C) Western blot analysis of ABCC2, ABCB1, ABCG2, and ABCC1 by curcumin and MMC with and without verapamil treatment in MDA-MB-231 BCSCs. Cells were incubated with 40 μmol/L curcumin, 25 μmol/L MMC, 10 μM/L verapamil and their combinations during 72 h. *P < 0.05 compared with MMC alone. (D) MDA-MB-231-derived BCSCs were treated with 40 μmol/L curcumin and 25 μmol/L MMC alone and together with and without fumitremorgin C and probenecid for 72 h. An MTT assay was performed. Values are mean ± SD from 3 independent experiments. *P < 0.05 compared with MMC alone.
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pone.0136694.g004: Effect of verapamil and curcumin on reversal of resistance to MMC in MDA-MB-231-derived BCSCs.(A) Cell survival was observed in MDA-MB-23-BCSCs and parental MDA-MB-231. Cells were treated with different concentrations for 48 h. *P < 0.05 compared with untreated control. (B) Dose- and time-dependent effect of MMC with and without verapamil and curcumin. *P < 0.05 compared with MMC and verapamil at corresponding doses. Cell survival was analyzed using MTT. Values are mean ± SD from 3 independent experiments. (C) Western blot analysis of ABCC2, ABCB1, ABCG2, and ABCC1 by curcumin and MMC with and without verapamil treatment in MDA-MB-231 BCSCs. Cells were incubated with 40 μmol/L curcumin, 25 μmol/L MMC, 10 μM/L verapamil and their combinations during 72 h. *P < 0.05 compared with MMC alone. (D) MDA-MB-231-derived BCSCs were treated with 40 μmol/L curcumin and 25 μmol/L MMC alone and together with and without fumitremorgin C and probenecid for 72 h. An MTT assay was performed. Values are mean ± SD from 3 independent experiments. *P < 0.05 compared with MMC alone.
Mentions: A hallmark of cancer stem cells is the enhanced ABC transporter expression that protects them from cytotoxic agent–induced damage. The observation that curcumin enhances the ability of MMC to induce BCSC cell death led to the hypothesis that curcumin modulated ABC transporter expression in BCSCs. To test this hypothesis, we first determined the IC50 of MMC in parental MDA-MB-231 cells and MDA-MB-231–derived BCSCs. An MTT viability assay showed a 6-fold increase in the IC50 of MMC in MDA-MB-231–derived BCSCs over their parental cells (Fig 4A). We subsequently examined the IC50 of MMC in MDA-MB-231–derived BCSCs with curcumin or verapamil. Verapamil reduced the IC50 of MMC from 50 to approximately 30 μmol/L, whereas curcumin reduced the IC50 to 20 μmol/L at 72 h (Fig 4B). We subsequently analyzed the effect of curcumin on ABC transporter levels in BCSCs through Western blotting; compared with untreated or MMC-treated cells, curcumin blocked 50% of ABCG2 and ABCC1 (Fig 4C). By contrast, verapamil did not significantly alter the expression of any of these ABC transporters (Fig 4C).

Bottom Line: MMC or curcumin alone only marginally reduced the BCSC population in the mammospheres; however, together, they reduced the BCSC population in CD44+CD24-/low cells by more than 75% (29.34% to 6.86%).Curcumin sensitized BCSCs through a reduction in the expression of ATP-binding cassette (ABC) transporters ABCG2 and ABCC1.We demonstrated that fumitremorgin C, a selective ABCG2 inhibitor, reduced BCSC survival to a similar degree as curcumin did.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

ABSTRACT
Cancer cells with stem cell-like properties contribute to the development of resistance to chemotherapy and eventually to tumor relapses. The current study investigated the potential of curcumin to reduce breast cancer stem cell (BCSC) population for sensitizing breast cancer cells to mitomycin C (MMC) both in vitro and in vivo. Curcumin improved the sensitivity of paclitaxel, cisplatin, and doxorubicin in breast cancer cell lines MCF-7 and MDA-MB-231, as shown by the more than 2-fold decrease in the half-maximal inhibitory concentration of these chemotherapeutic agents. In addition, curcumin sensitized the BCSCs of MCF-7 and MDA-MB-231 to MMC by 5- and 15-fold, respectively. The BCSCs could not grow to the fifth generation in the presence of curcumin and MMC. MMC or curcumin alone only marginally reduced the BCSC population in the mammospheres; however, together, they reduced the BCSC population in CD44+CD24-/low cells by more than 75% (29.34% to 6.86%). Curcumin sensitized BCSCs through a reduction in the expression of ATP-binding cassette (ABC) transporters ABCG2 and ABCC1. We demonstrated that fumitremorgin C, a selective ABCG2 inhibitor, reduced BCSC survival to a similar degree as curcumin did. Curcumin sensitized breast cancer cells to chemotherapeutic drugs by reducing the BCSC population mainly through a reduction in the expression of ABCG2.

No MeSH data available.


Related in: MedlinePlus