Study of combined effect of low-dose radiation or gallic acid with pirarubicin on multidrug resistance activities in leukemic K562 and K562/Dox cancer cells

Abstract

Leukemia is a common cancer that can be found worldwide. One of the anticancer drugs used to treat leukemia is pirarubicin (Pira). However, multidrug resistance (MDR) is an obstacle in the success of cancer treatment. This MDR is considered to be involved with P‑glycoprotein (P-gp), ATP‑dependent plasma membrane protein, and hence this mechanism is named as P-glycoprotein-mediated drug efflux. There are a lot of certain MDR‑reversing agents (cyclosporin A, verapamil and, tamoxifen) which are capable to reverse MDR in cancer cells. Unfortunately, these agents are associated with undesirable side effects. Therefore, an exploration of the alternative approach with better outcome to overcome MDR in cancer cells poses a new challenge. In cancer therapy, there are several studies to suggest the potential anticancer properties of natural products and one of them is gallic acid (GA). Gallic acid possesses the anticancer property in diverse types of cancer. The drug combination of GA with Pira may help to overcome MDR in cancer cells. Firstly, this research study intended to investigate the combined effect of Pira and GA on anticancer properties in leukemic K562 and K562/Dox (P-glycoprotein overexpression) cells and the possible mechanisms. The results indicated that GA and Pira combination decreased in cell viability, mitochondrial membrane potential (ΔΨm), mitochondrial activity and ATP levels in K562 and K562/Dox cells depending on the concentrations of GA. In addition, GA could inhibit the function of P-gp in K562/Dox cells. These findings suggested that GA could provide the improvement in the Pira‑induced anticancer activities in leukemic cell lines through the impairment of cellular energy status along with the MDR reversal effect in K562/Dox cells. In addition, anticancer approach for solid tumors is high-dose radiation therapy while low-dose radiation (LDR) for hematological cancers. Studies discovered the beneficial effects of LDR in normal cells, in contrast with the deleterious effect of LDR found in cancer cells including human leukemic cells. The second intention of this research was the examination of enhancing effect of LDR on anticancer properties of GA and Pira in the same cell lines. The experimental results suggested that pre low-dose irradiation followed by GA and Pira was unable to kill K562 and K562/Dox cells, but could increase the cellular energetic damage induced by GA and Pira, possibly through the mitochondrial dysfunction. Moreover, the efficacy of anticancer drugs is depended on several factors. One of them is the interaction between the drugs and proteins (human serum albumin and saliva protein). The third objective of this research was the analysis of the spectroscopic properties of saliva samples accumulated from normal individuals and oral cancer patients. In accordance with the detections in the auto-fluorescence emission spectra, synchronous spectra, absorption spectra, and metabolic profiles, the characteristic spectra of saliva samples were quite dissimilar between normal subjects and oral cancer patients. Taken together, it was possible to conclude that GA could enhance anticancer activity of Pira in K562 and K562/Dox cells through mitochondrial impairment. LDR did not affect on the anticancer activity of GA and Pira in both cells.