NADPH Oxidases as Therapeutic Targets in Chronic Myelogenous Leukemia

Abstract

Purpose: Cancer cells show higher levels of reactive oxygen species (ROS) than normal cells and increasing intracellular ROS levels are becoming a recognized strategy against tumor cells. Thus, diminishing ROS levels could be also detrimental to cancer cells. We surmise that avoiding ROS generation would be a better option than quenching ROS with antioxidants. Chronic myelogenous leukemia (CML) is triggered by the expression of BCR-ABL kinase, whose activity leads to increased ROS production, partly through NADPH oxidases. Here, we assessed NADPH oxidases as therapeutic targets in CML.Experimental Design: We have analyzed the effect of different NADPH oxidase inhibitors, either alone or in combination with BCR-ABL inhibitors, in CML cells and in two different animal models for CML.Results: NADPH oxidase inhibition dramatically impaired the proliferation and viability of BCR-ABLexpressing cells due to the attenuation of BCR-ABL signaling and a pronounced cell-cycle arrest. Moreover, the combination of NADPH oxidase inhibitors with BCR-ABL inhibitors was highly synergistic. Two different animal models underscore the effectiveness of NADPH oxidase inhibitors and their combination with BCR-ABL inhibitors for CML targeting in vivo.Conclusion: Our results offer further therapeutic opportunities for CML, by targeting NADPH oxidases. In the future, it would be worthwhile conducting further experiments to ascertain the feasibility of translating such therapies to clinical practice. Clin Cancer Res; 20(15); 4014-25. Ó2014 AACR.

CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia

“…Nuclei to the left of the 2N peak containing hypodiploid DNA were considered as apoptotic. Fluorescent microscopy and flow cytometric analysis of PI-stained nuclei were performed to evaluate cell cycle and viability by using a FACSCalibur cytometer and CellQuest software (BD Biosciences, Erembodegen, Belgium) [55]. Apoptosis was also determined by translocation of phosphatidylserine to the cell surface using the annexin V-FITC apoptosis detection kit (BD Pharmingen, Erembodegen, Belgium) according to the manufacturer’s protocol.…”

Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bioenergetics and energy-sensing mechanism

“…Previously, we have shown that Mito-CP and other mitochondria-targeted antioxidants inhibit Nox2 expression and activity in mice and inhibit nitration and carbonylation of proteins induced by NADPH oxidases (Nox) and inducible NOS [44,45]. Nox enzymes are emerging as a highly promising target for anticancer drug development [8,9]. Increasing evidence suggests that Noxderived ROS inhibits tumor apoptosis and stimulates tumor proliferation [8,9].…”

“…Nox enzymes are emerging as a highly promising target for anticancer drug development [8,9]. Increasing evidence suggests that Noxderived ROS inhibits tumor apoptosis and stimulates tumor proliferation [8,9]. It is plausible that indirect inhibition of Nox enzymes by Mito-CP and Mito-CP-Ac contributes to inhibition of tumor cell proliferation.…”

“…Of the several sources of ROS generation pathways, membrane-associated NADPH oxidase (Nox) family of enzymes and mitochondria are recognized as major contributors of ROS in tumor cells [8,9]. More recently, we and others have shown that several structurally and functionally-distinct groups of mitochondria-targeted antioxidants [e.g., Mito-Q, triphenylphosphonium cation (TPP + ) conjugated to Co-Q; Mito-CP, TPP + conjugated to 3-carboxyproxyl nitroxide; Mito-Vitamin-E or Mito-chromanol, TPP + conjugated to Vitamin-E analog] inhibit tumor cell proliferation in vitro and attenuate tumor growth in vivo [10–13].…”

Therapeutic potential of NADPH oxidase 1/4 inhibitors

“…NOX, particularly NOX4, have also been implicated in resistance to target therapies (Liu‐Smith et al , ; Sanchez‐Sanchez et al , ), anti‐hormonal therapies (Lu et al , ) and cytotoxics (Chang et al , ) as well as radiotherapy (Hsieh et al , ; Li et al , ), indicating that NOX inhibitors might enhance the efficacy of current cancer treatments.…”