ASCORBIC ACID - MODULATION OF ARSENIC TRIOXIDE TOXICITY: IMPLICATION FOR THE CLINICAL TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA.

Abstract

Background: Acute Promyelocytic Leukemia (APL) is a subtype of acute leukemia which can affect people of any age. It strikes about 1,500 patients in the United States each year. Recent in vitro and in vivo studies have shown that arsenic trioxide (ATO) can induce clinical remission in de-novo and APL patients that have relapsed from conventional treatment. Ascorbic acid (AA) is an anti-oxidant and free radical scavenger effective against peroxyl- and hydroxyl-radicals, superoxide, singlet oxygen and peroxynitrite. Although research has shown that AA can prevent cancer by deactivating free radicals before they can damage DNA and initiate tumor growth, there are also published reports indicating that it may act as a pro-oxidant that helps the body's own free radical defense mechanism destroy tumors in their early stages.

Aim: The aim of this research was to study the modulatory effect of AA on ATO-induced oxidative stress in leukemia cells.

Methods: In the present investigation, we performed the MTT assay and trypan blue exclusion test for cell viability. We also performed the thiobarbituric acid test to determine the levels of malondialdehyde (MDA) production in HL-60 cells co-exposed to ascorbic acid (AA) and ATO.

Results: The results of MTT assay indicated that AA exposure potentiates the cytotoxicity of ATO in HL-60 cells, as evidenced by a gradual increase in MDA levels with increasing doses of AA. From these results, we concluded that the addition of the ascorbic acid to ATO-treated HL-60 cells enhances the formation of reactive oxygen species (ROS).

Conclusions: Based on these direct in vitro findings, our study provides evidence that AA may extend the therapeutic spectrum of ATO, and improve the clinical outcome associated with ATO monotherapy in vivo.