Gallic acid enhances pirarubicin‑induced anticancer in living K562 and K562/Dox leukemia cancer cells through cellular energetic state impairment and P‑glycoprotein inhibition

Abstract

Leukemia is a common malignancy affecting humans worldwide. Pirarubicin (Pira) is one of the anticancer agents used for the treatment of leukemia. Although Pira is effective, drug resistance may develop in cancer cells exposed to this drug, whereas the combination of natural products with Pira may help to overcome this problem. The aim of the present study was to focus on the effect of gallic acid (GA) on the anticancer activity of Pira in K562 leukemia cells and K562/doxorubicin (Dox)-resistant leukemia cells in order to investigate the possible underlying mechanisms. The cell viability, mitochondrial activity, mitochondrial membrane potential (ΔΨm) and ATP levels were assessed in living K562 and K562/Dox cancer cells following treatment with GA/Pira combination, GA alone or Pira alone. P-glycoprotein-mediated efflux of Pira was determined in GA-treated K562/Dox cancer cells. The results demonstrated that GA/Pira combination decreased cell viability, mitochondrial activity, ΔΨm and ATP levels in K562 and K562/Dox cancer cells in a GA concentration-dependent manner compared with non-treated or Pira-treated cells. GA inhibited P-glycoprotein-mediated efflux of Pira in GA-treated K562/Dox cancer cells. Therefore, GA enhanced the anticancer effect of Pira on K562 and K562/Dox cancer cells through cellular energy status impairment, and was able to reverse drug resistance in living K562/Dox cancer cells by inhibiting the function of P-glycoprotein.

Modulation of p-glycoprotein-mediated efflux pirarubicin in living multidrug-resistant K562/Dox cell lines by 4-hydroxybenzoic acid and 4-hydroxy-3-methoxybenzoic acid via impairment of the cellular energetic state

“…The cellular ATP was measured in ways consistent with previous reports [27] . Briefly, 2 × 10 6 cells/mL were treated with 0.01, 0.1, 1, and 10 mM 4-HBA or VA for 30, 60, 120, 240 min in a HEPES-Na + buffer, having a pH of 7.25 at a temperature of 37 °C.…”

“…The assay was used to evaluate the mitochondrial activity based on directions indicated in a previous report [27] . Briefly, 5 × 10 5 cell/mL were treated with 0.01, 0.1, 1, and 10 mM 4-HBA or VA in a completed RPMI-1640 medium in a cell culture incubator for 5, 10, 30, 60, 120, and 240 min.…”

“…A non-invasive functional spectrofluorometric approach was used to determine the ΔΨm based on previous reports [25] , [27] , [28] . Briefly, 2 × 10 6 cells/mL were treated with 0.01, 0.1, 1, and 10 mM 4-HBA or VA for 5, 10, 30, 60, 120, and 240 min in HEPES-Na + buffer, pH 7.25 at a temperature of 37 °C and then this was followed by an addition of 40 nM concentration of Rho B.…”

NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress

“…INTRODUCTION Doxorubicin (DOX) is an antitumor chemotherapeutic agent widely used in clinical practice [1][2][3], but its cardiotoxicity can lead to tumor treatment failure or even death. Statistics from recent years show that the incidence and mortality of cardiac toxicity are much more serious than we expected [4].…”

An update on the potential mechanism of gallic acid as an antibacterial and anticancer agent

“…In GA‐treated K562/Dox cancer cells, GA suppressed P‐glycoprotein‐mediated efflux of Pira. Also, GA increased the antitumor effect of Pira on K562 and K562/Dox cancer cells by disrupting cellular energy status and reversing drug resistance in live K562/Dox cancer cells by blocking P‐glycoprotein function (Aye et al, 2021 ).…”