Cytotoxic Effects of Some Flavonoids and Imatinib on K562 Chronic Myeloid Leukemia Cell Line: Data Analysis Using the Combination Index Method

Abstract

Background: Flavonoids are natural compounds with antioxidant, anticarcinogenic, and anti-inflammatory effects. Aims: To determine the cytotoxic effects of flavonoids and drug resistance related to P-gp on K562 human chronic myeloid leukemia cells. We also aimed to evaluate the therapeutic potential of imatinib and flavonoid combinations. Study Design: Cell culture study. Methods: In this study, K562 cells were treated with apigenin, luteolin, 5-desmethyl sinensetin and the anticancer drug imatinib mesylate. The effect of flavonoids on K562 cell proliferation was detected using the 3-(4,5-dimethylthiazolyl)2,5-diphenyl-tetrazolium bromide assay. Concentrations of apigenin, luteolin, and 5-desmethyl sinensetin ranging from 25 to 200 μM and of imatinib from 5 to 50 μM administered for 72 h were studied. Apoptosis/necrosis and P-gp activity were measured using flow cytometry. The combined effects of different concentrations of flavonoids with imatinib were evaluated according to combination index values calculated using CompuSyn software. Results: In our study, the IC 50 values for apigenin, luteolin, and 5-desmethyl sinensetin were found to be 140 μM, 100 μM, and >200 μM, respectively. Luteolin (100 μM) had the highest cytotoxic activity of these flavonoids. These results were statistically significant (p<0.05). Among the flavonoids studied, the combination of luteolin and imatinib was the most effective and is therefore recommended for its cytotoxic activity in the K562 cell line. After 72 h of incubation at their respective IC 50 concentrations, all flavonoids were associated with an apoptosis rate of approximately 50%. P-glycoprotein activity was increased in all groups. Combination treatment may provide better outcomes in terms of cytotoxicity and thus reduce the dosages of imatinib used. Conclusion: The combination of some flavonoids and imatinib mesylate may increase the cytotoxic effect; However, the antagonistic effect should be considered in combined use on k562 cells.

Thymoquinone chemosensitizes human colorectal cancer cells to imatinib via uptake/efflux genes modulation

“…ATP‐binding cassette (ABC) transporters, such as the ABC subfamily G member 2 (ABCG2; formerly known as breast cancer resistance protein [BCRP]) and the ABC subfamily B member 1 (ABCB1; formerly known as P‐glycoprotein or MDR1), are IM efflux transporters 16 . The multidrug resistance (MDR) related to increased expression of efflux pumps, is one of the important mechanisms of resistance 17 . In addition, the decrease in influx transporters, such as the drug uptake transporter human organic cation transporter 1 (hOCT1), has also emerged as a mechanism responsible for inefficient drug uptake and consequent treatment failure 18,19 .…”

“…16 The multidrug resistance (MDR) related to increased expression of efflux pumps, is one of the important mechanisms of resistance. 17 In addition, the decrease in influx transporters, such as the drug uptake transporter human organic cation transporter 1 (hOCT1), has also emerged as a mechanism responsible for inefficient drug uptake and consequent treatment failure. 18,19 Notably, after oral administration, IM has an excellent bioavailability that exceeds 90%, but its efflux from the cell remains the main cause of resistance.…”