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

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

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Abstract

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- and 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-and 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.

Item Type: Article
Uncontrolled Keywords: CANCER DRUG-RESISTANCE; MULTIDRUG-RESISTANCE; BREAST-CANCER; SHIKONIN DERIVATIVES; MESSENGER-RNA; PROTEIN; ANALOGS; TRANSPORTERS; INHIBITION; EXPRESSION
Subjects: QU Biochemistry
QZ pathology-Neoplasms
Divisions: Faculty of Medicine > Basic Sciences Academic Groups > Department of Biochemistry and Genetics
Depositing User: zahra bagheri .
Date Deposited: 20 Sep 2018 14:19
Last Modified: 20 Sep 2018 14:19
URI: http://eprints.skums.ac.ir/id/eprint/7232

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