Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Abstract

The past decade has seen an exponential increase in the number of cancer therapies with defined molecular targets. Interestingly, many of these new agents are also documented to raise levels of intracellular reactive oxygen species (ROS) in addition to inhibiting a biochemical target. In most cases, the exact link between the primary target of the drug and effects on cellular redox status is unknown. However, it is important to understand the role of oxidative stress in promoting cytotoxicity by these agents, because the design of multiregimen strategies could conceivably build on these redox alterations. Also, drug resistance mediated by antioxidant defenses could potentially be anticipated and circumvented with improved knowledge of the redoxrelated effects of these targeted agents. Given the large number of targeted chemotherapies, in this review, we focus on selected agents that have shown promise in hematologic malignancies: proteasome inhibitors, histone deacetylase inhibitors, Bcl-2-targeted agents, and a kinase inhibitor called adaphostin. Despite structural differences within classes of these compounds, a commonality of causing increased oxidative stress exists, which contributes to induction of cell death. Antioxid. Redox Signal. 11, 1123-1137.

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

“…9 We therefore asked whether bortezomib induces ROS in K562 and OCI-AML3 cells, and whether ROS activation is related to bortezomib-induced apoptosis. As shown in Figure 2a, bortezomib treatment stimulated an increase in the superoxide-specific DHE-derived fluorescence 36 (Figure 2a), but not in the hydrogen peroxide dye DCFDA-H2 derived fluorescence 36 (Figure 2b), indicating that bortezomib increases the production of superoxide but not of hydrogen peroxide in these cells.…”

“…5 Bortezomib, a specific inhibitor of the 20S proteasome, has displayed clinical efficacy in a number of hematologic malignancies. [8][9][10][11][12] In addition to its direct inhibitory effects on the proteasome, 9 bortezomib has been noted to increase the level of intracellular reactive oxygen species (ROS) as an important component of its ability to induce apoptosis, [13][14][15][16][17][18] autophagy [19][20][21] and differentiation. 22 A sustained increase in ROS generation appears, in turn, to enhance the inhibitory effects of bortezomib on proteasomal activity.…”

“…22 A sustained increase in ROS generation appears, in turn, to enhance the inhibitory effects of bortezomib on proteasomal activity. 9 It has also been postulated that the bortezomib-induced increases in ROS levels in tumor cells may be the basis for its synergy with other chemotherapeutic agents. 9,23 Arsenic trioxide (ATO) has emerged as the most active single agent in the treatment of acute promyelocytic leukemia, 24 and ATO-based therapies are being investigated in other cancers including other hematopoietic malignancies.…”

“…9 It has also been postulated that the bortezomib-induced increases in ROS levels in tumor cells may be the basis for its synergy with other chemotherapeutic agents. 9,23 Arsenic trioxide (ATO) has emerged as the most active single agent in the treatment of acute promyelocytic leukemia, 24 and ATO-based therapies are being investigated in other cancers including other hematopoietic malignancies. [25][26][27][28][29] Although the mechanisms underlying ATO-induced cytotoxicity are not completely understood, ATO-mediated induction of ROS has been shown to reduce the membrane potential of mitochondria, enhance the release of cytochrome c and induce both caspasedependent and caspase-independent apoptosis.…”

Effects of Epigenetic Drugs (Vorinostat, Decitabine) on Metabolism-Related Pathway Factors in Leukemic Cells~!2010-02-03~!2010-03-25~!2010-05-17~!

“…Although, the present report appears to be the first study, showing the metabolic effects of epigenetically active drugs, downregulatory effects on carbohydrate metabolism have been expected both with SAHA and DAC as a consequence of induced mitochondrial damage [34][35][36][37]. In addition, both these pharmacologic compounds are also known for their antiproliferative effects resulting from cell cycle inhibition [3,4].…”