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Reversal of human multi-drug resistance leukaemic cells by stemofoline derivatives via inhibition of P-glycoprotein function.

Basic & clinical pharmacology & toxicology (2014-09-30)
Sonthaya Umsumarng, Pornsiri Pitchakarn, Kwankamol Sastraruji, Supachai Yodkeeree, Alison T Ung, Stephen G Pyne, Pornngarm Limtrakul
ABSTRACT

Our previous study reported multi-drug resistance (MDR) reversing properties of synthetic stemofoline derivatives (STFD), OH-A1, NH-B6 and NH-D6 on P-glycoprotein (P-gp) overexpressing leukaemic cells (K562/Adr); however, the mechanism was unclear. In this study, we further investigated whether the STFD reverse MDR through either the inhibition of P-gp function or expression in K562/Adr cells, or both. The P-gp functional studies showed that the STFD increased the accumulation of calcein-AM, rhodamine 123 and [(14) C]-doxorubicin in K562/Adr cells, while the effects have not been seen in their parental sensitive cancer cell line (K562). Further, the STFD did not alter the P-gp expression as determined by Western blotting. This study concludes that the STFD reverse MDR via the inhibition of P-gp function. The efficacy of the STFD to inhibit P-gp function followed the order: NH-B6 > OH-A1 > NH-D6. These compounds could be introduced as candidate molecules for treating cancers exhibiting P-gp-mediated MDR.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Doxorubicin hydrochloride, 98.0-102.0% (HPLC)
Sigma-Aldrich
Cyclosporin A, 97.0-101.5% (on dried basis)
Sigma-Aldrich
Doxorubicin hydrochloride, suitable for fluorescence, 98.0-102.0% (HPLC)
Sigma-Aldrich
Calcein-AM, BioReagent, suitable for fluorescence, ≥95.0% (HPLC)
Sigma-Aldrich
Cyclosporin A, from Tolypocladium inflatum, BioReagent, for molecular biology, ≥95%
Supelco
Cyclosporin A, VETRANAL®, analytical standard
Sigma-Aldrich
Cyclosporin A, from Tolypocladium inflatum, ≥95% (HPLC), solid
USP
Doxorubicin hydrochloride, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Calcein-AM, Small Package (20 X 50 μg ), ≥95.0% (HPLC)
Doxorubicin hydrochloride, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Rhodamine 123, mitochondrial specific fluorescent dye
Sigma-Aldrich
Calcein AM solution, 4 mM in DMSO, ≥90% (HPLC), solution
Sigma-Aldrich
Rhodamine 123, BioReagent, for fluorescence, ≥85% (HPLC)
Supelco
Cyclosporine, Pharmaceutical Secondary Standard; Certified Reference Material