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Curcumin and its Analogues (PGV-0 and PGV-1) Enhance Sensitivity of Resistant MCF-7 Cells to Doxorubicin through Inhibition of HER2 and NF-kB Activation

  • Meiyanto, Edy (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada) ;
  • Putri, Dyaningtyas Dewi Pamungkas (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada) ;
  • Susidarti, Ratna Asmah (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada) ;
  • Murwanti, Retno (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada) ;
  • Sardjiman, Sardjiman (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada) ;
  • Fitriasari, Aditya (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada) ;
  • Husnaa, Ulfatul (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada) ;
  • Purnomo, Hari (Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada) ;
  • Kawaichi, Masashi (Lab Of Gene Function, School of Biosciences, Nara Institute of Science and Technology)
  • Published : 2014.01.15

Abstract

Chemoresistance of breast cancer to doxorubicin is mediated mainly through activation of NF-kB and over expression of HER2. Curcumin and its analogues (PGV-0 and PGV-1) exert cytotoxic effects on T47D breast cancer cells. Suppression of NF-kB activation is suggested to contribute to this activity. The present study aimed to explore the effects of curcumin, PGV-0, and PGV-1 singly and in combination with doxorubicin on MCF-7/Dox cells featuring over-expression of HER2. In MTT assays, curcumin, PGV-0, and PGV-1 showed cytotoxicity effects against MCF-7/Dox with IC50 values of $80{\mu}M$, $21{\mu}M$, and $82{\mu}M$ respectively. These compounds increased MCF-7/Dox sensitivity to doxorubicin. Cell cycle distribution analysis exhibited that the combination of curcumin and its analogues with Dox increased sub G-1 cell populations. Curcumin and PGV-1 but not PGV-0 decreased localization of p65 into the nucleus induced by Dox, indicating that activation of NF-kB was inhibited. Molecular docking of curcumin, PGV-0, and PGV-1 demonstrated high affinity to HER2 at ATP binding site. This interaction were directly comparable with those of ATP and lapatinib. These findings suggested that curcumin, PGV-0 and PGV-1 enhance the Dox cytotoxicity to MCF-7 cells through inhibition of HER2 activity and NF-kB activation.

Keywords

Curcumin and its analogues;HER2;MCF-7/Dox cells;NF-kB

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