Antioxidants block proteasome inhibitor function in endometrial carcinoma cells

Llobet, David; Eritja, Núria; Encinas, Mario; Sorolla, Anabel; Yeramian, Andrée; Schoenenberger, Joan Antoni; Llombart-Cussac, Antonio; Martí, Rosa M.; Matías‐Guiu, Xavier; Dolcet, Xavier

doi:10.1097/cad.0b013e3282f24031

Cited by 55 publications

(42 citation statements)

References 22 publications

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“…As noted above, proteasome inhibitors can induce significant oxidative stress (ROS); furthermore, cells exposed to proteasome inhibitors can be rescued by various antioxidants, including NAC (Ling et al, 2003;Fribley et al, 2004;Minami et al, 2005;Llobet et al, 2008). Moreover, proteasome inhibitors can also induce Bax and JNK activation (Dai et al, 2003;Dewson et al, 2003;Yu et al, 2003;Yang et al, 2004).…”

Section: Discussionmentioning

confidence: 97%

Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells

et al. 2009

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Naturally occurring triterpenoid compounds have long been used as anti-inflammatory, antimalarial, and insecticidal agents. It has become evident that some of the natural or synthetic triterpenoids have promising clinical potential as both a therapeutic and chemopreventive agent for cancer. However, the molecular basis for the antitumor activity of triterpenoid has yet to be defined. In this study, we show that pristimerin, a natural triterpenoid, induces mitochondrial cell death in human cervical cancer cells and that reactive oxygen species (ROS)-dependent activation of both Bax and poly(ADP-ribose) polymerase-1 (PARP-1) is critically required for the mitochondrial dysfunction. We also showed that c-Jun N-terminal kinase (JNK) is involved in ROS-dependent Bax activation. Treatment of pristimerin induced an increase in intracellular ROS, JNK activation, conformational change, and mitochondrial redistribution of Bax, mitochondrial membrane potential loss, and cell death. The PARP-1 was also found to be activated by pristimerin treatment. An antioxidant, N-acetyl-L-cysteine (NAC), inhibited pristimerin-induced JNK activation, Bax relocalization, and PARP-1 activation, as well as mitochondrial cell death. Moreover, inhibition of JNK clearly suppressed conformational change and mitochondrial translocation of Bax and subsequent mitochondrial cell death but did not affect PARP-1 activation. Inhibition of PARP-1 with 1,5-dihydroxyisoquinoline (DIQ) or with small interfering RNA of PARP-1 significantly attenuated pristimerininduced mitochondrial membrane potential loss and cell death but did not affect JNK activation and Bax relocalization. These results indicate that the natural triterpenoid pristimerin induces mitochondrial cell death through ROS-dependent activation of both Bax and PARP-1 in human cervical cancer cells and that JNK is involved in ROS-dependent Bax activation.

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Section: Discussionmentioning

confidence: 97%

Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells

et al. 2009

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“…Many other studies have probed the role of ROS in bortezomib-induced cell death in model systems, including myeloma (83), mantle cell lymphoma (85), and leukemia (71), as well as solid tumor models like colon cancer (72), endometrial cancer (62), and head and neck squamous cell carcinoma (29). Across the hematologic malignancy models, the ability of bortezomib to increase ROS appears conserved, with a number of different antioxidants, such as NAC, showing cytoprotection.…”

Section: Proteasome Inhibitorsmentioning

confidence: 99%

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Chandra

2009

Antioxidants & Redox Signaling

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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.

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“…Importantly, earlier studies have shown that vitamin C blocks the activity of bortezomib in vitro by its direct binding to bortezomib. [25][26][27] In addition, production of reactive oxygen species by bortezomib 28 is reduced by vitamin C. 29 However, the clinical significance of vitamin C intake in MM patients receiving bortezomib treatment remains unclear. Our study confirms that vitamin C as a dietary supplement can inhibit anti-MM activity of bortezomib in vivo.…”

Section: Introductionmentioning

confidence: 99%

Ascorbic acid inhibits antitumor activity of bortezomib in vivo

et al. 2009

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Earlier studies have shown that ascorbic acid (vitamin C) inhibits bortezomib-induced cytotoxicity against cancer cells in vitro. However, the clinical significance of vitamin C on bortezomib treatment is unclear. In this study, we examined whether daily oral intake of vitamin C inhibits antimultiple myeloma (MM) activities of bortezomib. Vitamin C, at orally achievable concentrations, inhibited in vitro MM cell cytotoxicity of bortezomib and blocked its inhibitory effect on 20S proteasome activity. Specifically, plasma collected from healthy volunteers taking 1 g/day vitamin C reduced bortezomibinduced MM cell death in vitro. This antagonistic effect of vitamin C against proteasome inhibitors is limited to the boronate class of inhibitors (bortezomib and MG262). In vivo activity of this combination treatment was then evaluated using our xenograft model of human MM in SCID (severe combined immune-deficient) mice. Bortezomib (0.1 mg/kg twice a week for 4 weeks) significantly inhibits in vivo MM cell growth, which was blocked by oral vitamin C (40 mg/kg/day). Therefore, our results for the first time show that vitamin C can significantly reduce the activity of bortezomib treatment in vivo; and importantly, suggest that patients receiving treatment with bortezomib should avoid taking vitamin C dietary supplements.

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Antioxidants block proteasome inhibitor function in endometrial carcinoma cells

Cited by 55 publications

References 22 publications

Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells

Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Ascorbic acid inhibits antitumor activity of bortezomib in vivo

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