Broad blocking of MDR efux pumps by acetylshikonin and acetoxyisovalerylshikonin to generate hypersensitive phenotype of malignant carcinoma cells

Mirzaei, Seyed Abbas. and Reiisi, Somayeh. and Ghiasi Tabari, Parmida. and Shekari, Abolfazl. and Aliakbari, Fatemeh. and Azadfallah, Elahe. and Elahian, Fatemeh. (2018) Broad blocking of MDR efux pumps by acetylshikonin and acetoxyisovalerylshikonin to generate hypersensitive phenotype of malignant carcinoma cells. Scientific Reports., 8 (1).

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Abstract

Cytotoxic activities of acetylshikonin and acetoxyisovalerylshikonin alone and in combination with chemotherapeutic agents against parental and drug resistant cell lines were determined using the MTT assay. Effects of Shikonin derivatives on BCRP, MDR1 and MRP transcript and protein levels were relatively measured. Finally, accumulation and efflux kinetics were conducted. The results revealed cell- A nd concentration-dependency of the cell cytotoxicity. Acetylshikonin and acetoxyisovalerylshikonin transiently made the mRNA ocean turbulent, but FACS analyses using fluorescent-labeled antibodies showed no significant change in the MDR-protein levels. Functional kinetics revealed significant block of MDR1, BCRP and MRP transporter in the presence of shikonin derivatives. Maximum accumulation fold changes was quantified to be 4.4 and consequently, acetoxyisovalerylshikonin pretreated EPG85.257RDB cells was chemosensitized to daunorubicin tension 3.1-fold. Although, the MDR blockage was reported to follow time- A nd cell-dependent patterns, MDR1, BCRP and MRP2 responses to the shikonins are concentration-independent. These data suggest uncompetitive transporter blockage behavior of these agents. The results indicated that shikonin derivatives stimulate uptake and reduce efflux of chemotherapeutic agents in the malignant cancer cells, suggesting that chemotherapy in combination with shikonin compounds may be beneficial to cancer cells that overexpress multidrug resistance transporters. © 2018 The Author(s).

Item Type: Article
Subjects: QZ pathology-Neoplasms
QU Biochemistry > Cell biology and genetics
Divisions: Reserach Vice-Chancellar Department > Cellular and Molecular Research Center
Depositing User: zahra bagheri .
Date Deposited: 25 Aug 2018 04:03
Last Modified: 25 Aug 2018 04:03
URI: http://eprints.skums.ac.ir/id/eprint/6995

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