Reversal of Multidrug Resistance in Mouse Lymphoma Cells by Extracts and Flavonoids from Pistacia integerrima.

Abdur Rauf,Bashir Ahmad,Noor Jehan,Akos Csonka,Muslim Raza,Ghias Uddin,Bina S Siddiqui,Diana Szabo,Joseph Molnar

doi:10.7314/apjcp.2016.17.1.51

Abstract

Phytochemical investigation of Pistacia integerrima has highlighted isolation of two known compounds naringenin (1) and dihydrokaempferol (2). A crude extract and these isolated compounds were here evaluated for their effects on reversion of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). The multidrug resistance P-glycoprotein is a target for chemotherapeutic drugs from cancer cells. In the present study rhodamine- 123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma cells showed excellent MDR reversing effects in a dose dependent manner. In-silico molecular docking investigations demonstrated a common binding site for Rhodamine123, and compounds naringenin and dihydrokaempferol. Our results showed that the relative docking energies estimated by docking softwares were in satisfactory correlation with the experimental activities. Preliminary interaction profile of P-gp docked complexes were also analysed in order to understand the nature of binding modes of these compounds. Our computational investigation suggested that the compounds interactions with the hydrophobic pocket of P-gp are mainly related to the inhibitory activity. Moreover this study s a platform for the discovery of novel natural compounds from herbal origin, as inhibitor molecules against the P-glycoprotein for the treatment of cancer.

Highlights

Multidrug resistance (MDR) is the main clinical challenge for the active treatment of cancer (Szabo and Molnar, 1997)
The ATP-binding cassette (ABC) transporters represent the largest family of transmembrane proteins that bind ATP and use the energy to drive the transport of various molecules across cell membranes (Gottesman and Ambudkar, 2001; Leonard et al, 2003)
Several studies have demonstrated the frequent occurrence of drug efflux proteins in cancer tissue: some authors have reported significant correlations between overexpression of ABCB1 or MRP-1 and poor treatment response in solid tumors and some leukemias (Brinkhuis et al, 2002; Diestra et al, 2003) (Larkin et al, 2004; Damiani et al, 2006), and a prognostic significance for Breast Cancer Resistance Protein (BCRP) overexpression in specific forms of leukemia (Larkin et al, 2004)

Summary

Introduction

Multidrug resistance (MDR) is the main clinical challenge for the active treatment of cancer (chemotherapy) (Szabo and Molnar, 1997). A crude extract and these isolated compounds were here evaluated for their effects on reversion of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). The multidrug resistance P-glycoprotein is a target for chemotherapeutic drugs from cancer cells.

Results

Conclusion