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

Scientific Reports
Seyed Abbas MirzaeiFatemeh Elahian

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 der...Continue Reading

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Citations

Feb 26, 2020·International Journal of Molecular Sciences·Jingqiu WangZhe-Sheng Chen
Jan 19, 2020·Nature Reviews. Urology·Julieta AfonsoFátima Baltazar
Sep 22, 2020·Pharmaceutical Biology·Zhiqin ZhangJian Ni
Mar 17, 2020·Frontiers in Oncology·Jingqiu WangZhe-Sheng Chen
Aug 3, 2019·European Journal of Medicinal Chemistry·Lucia BiasuttoMario Zoratti
Sep 9, 2019·Life Sciences·Seyed Abbas MirzaeiFatemeh Elahian
Aug 23, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Manendra Singh TomarAshutosh Shrivastava

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Methods Mentioned

BETA
PCR
FACS

Software Mentioned

FlowJo
SPSS
WinMDI

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