Targeting Catalase but Not Peroxiredoxins Enhances Arsenic Trioxide-Induced Apoptosis in K562 Cells

Abstract

Despite considerable efficacy of arsenic trioxide (As2O3) in acute promyelocytic leukemia (APL) treatment, other non-APL leukemias, such as chronic myeloid leukemia (CML), are less sensitive to As2O3 treatment. However, the underlying mechanism is not well understood. Here we show that relative As2O3-resistant K562 cells have significantly lower ROS levels than As2O3-sensitive NB4 cells. We compared the expression of several antioxidant enzymes in these two cell lines and found that peroxiredoxin 1/2/6 and catalase are expressed at high levels in K562 cells. We further investigated the possible role of peroxirdoxin 1/2/6 and catalase in determining the cellular sensitivity to As2O3. Interestingly, knockdown of peroxiredoxin 1/2/6 did not increase the susceptibility of K562 cells to As2O3. On the contrary, knockdown of catalase markedly enhanced As2O3-induced apoptosis. In addition, we provide evidence that overexpression of BCR/ABL cannot increase the expression of PRDX 1/2/6 and catalase. The current study reveals that the functional role of antioxidant enzymes is cellular context and treatment agents dependent; targeting catalase may represent a novel strategy to improve the efficacy of As2O3 in CML treatment.

Cellular and molecular alterations induced by low‑dose fisetin in human chronic myeloid leukemia cells

“…As shown in Fig. 7A, a single treatment with ATO, at concentrations ranging from 0.5 to 2.5 µ M, had little if any effect on the viability of the K562 cells, the results of which are consistent with those of previous studies on this cell line (54,55). In turn, the combination of FIS and ATO produced a highly variable effect on cell survival in dependence of the concentrations of both agents.…”

“…ATO is known for its high in vitro and clinical activity against acute promyelocytic leukemia (APL), and numerous preclinical data have also supported its role as a therapy for CML (92,93). ATO treatment has been shown to present similar cellular effects on CML cell lines as on APL ones, although higher and clinically unachievable concentrations are required to promote the cell cycle arrest and apoptosis of the former leukemia cells (54,55,94,95). Therefore, there has been a rationale for the development of optimized ATO-based combination regimens to maintain or potentiate a treatment response, while reducing its dosage to sub-pharmacological, non-toxic levels (95-98).…”

Biochanin A Ameliorates Arsenic-Induced Hepato- and Hematotoxicity in Rats

“…On the other hand, SOD and CAT are enzymatic antioxidants that function mutually to eliminate free radicals produced during arsenic exposure [33]. SOD catalyzes the reduction of superoxide radical into hydrogen peroxide, while CAT reduces hydrogen peroxide into water and oxygen [34].…”

Peroxisomal Hydrogen Peroxide Metabolism and Signaling in Health and Disease

“…Indeed, chronic reduction of CAT activity in human cells has been documented to increase oxidative damage, enhance the secretion of matrix metalloproteinases, and impair mitochondrial function (see Section 4.2.3) (Figure 3) [122]. In addition, there is strong evidence that CAT can act as a protectant against apoptosis induced by multiple types of oxidative insults (e.g., ultraviolet and ionizing radiation [123,124], arsenic trioxide treatment [125], or P53-induced oxidative stress [126]). Also, peroxisomally located PRDX5 has been shown to have a cytoprotective effect against H 2 O 2 -induced cytotoxicity [127].…”