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Epoxyeicosatrienoic acids attenuate reactive oxygen species level, mitochondrial dysfunction, caspase activation, and apoptosis in carcinoma cells treated with arsenic trioxide.

ABSTRACT: Epoxyeicosatrienoic acids (EETs) and the cytochrome P450 epoxygenase CYP2J2 promote tumorogenesis in vivo and in vitro via direct stimulation of tumor cell growth and inhibition of tumor cell apoptosis. Herein, we describe a novel mechanism of inhibition of tumor cell apoptosis by EETs. In Tca-8113 cancer cells, the antileukemia drug arsenic trioxide (ATO) led to the generation of reactive oxygen species (ROS), impaired mitochondrial function, and induced apoptosis. 11,12-EET pretreatment increased expression of the antioxidant enzymes superoxide dismutase and catalase and inhibited ATO-induced apoptosis. 11,12-EET also prevented the ATO-induced activation of p38 mitogen-activated protein kinase, c-Jun NH(2)-terminal kinase, caspase-3, and caspase-9. Therefore, 11,12-EET-pretreatment attenuated the ROS generation, loss of mitochondrial function, and caspase activation observed after ATO treatment. Moreover, the CYP2J2-specific inhibitor compound 26 enhanced arsenic cytotoxicity to a clinically relevant concentration of ATO (1-2 μM). Both the thiol-containing antioxidant, N-acetyl-cysteine, and 11,12-EET reversed the synergistic effect of the two agents. Taken together, these data indicate that 11,12-EET inhibits apoptosis induced by ATO through a mechanism that involves induction of antioxidant proteins and attenuation of ROS-mediated mitochondrial dysfunction.

SUBMITTER: Liu L

PROVIDER: S-EPMC3199997 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Reactive oxygen species are not required for an arsenic trioxide-induced antioxidant response or apoptosis.

Project description:Arsenicals are both environmental carcinogens as well as therapeutic agents for the treatment of trypanosomiasis and more recently cancer. Arsenic trioxide (ATO) has been successfully used for the treatment of acute promyelocytic leukemia (APL) and has activity in multiple myeloma (MM). While signaling events associated with carcinogenesis have been well studied, it still remains to be determined which of these events are involved in anti-cancer signaling. To better define this response, gene expression profiling following ATO treatment of four MM cell lines was performed. The pattern was consistent with a strong antioxidative response, particularly of genes activated by Nrf2. While Nrf2 is expressed constitutively at the mRNA level, the protein is not detected in untreated cells. Consistent with inactivation of Keap1, Nrf2 protein is stabilized and present in the nucleus within 6 h of ATO treatment. Despite the activation of this antioxidative response, ROS may not be important in ATO-induced death. Inhibition of ATO-induced ROS with butylated hydroxyanisole (BHA) does not affect Nrf2 activation or cell death. Moreover, silencing Nrf2 had no effect on ATO-induced apoptosis. Together these data suggest that ROS is not important in the induction of the antioxidative response or cellular death by ATO.

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The Role of Reactive Oxygen Species in Arsenic Toxicity.

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CYP2J2 metabolites, epoxyeicosatrienoic acids, attenuate Ang II-induced cardiac fibrotic response by targeting G?<sub>12/13</sub>.

Project description:The arachidonic acid-cytochrome P450 2J2-epoxyeicosatrienoic acid (AA-CYP2J2-EET) metabolic pathway has been identified to be protective in the cardiovascular system. This study explored the effects of the AA-CYP2J2-EET metabolic pathway on cardiac fibrosis from the perspective of cardiac fibroblasts and underlying mechanisms. In in vivo studies, 8-week-old male CYP2J2 transgenic mice (aMHC-CYP2J2-Tr) and littermates were infused with angiotensin II (Ang II) or saline for 2 weeks. Results showed that CYP2J2 overexpression increased EET production. Meanwhile, impairment of cardiac function and fibrotic response were attenuated by CYP2J2 overexpression. The effects of CYP2J2 were associated with reduced activation of the ? subunits of G12 family G proteins (G?12/13)/RhoA/Rho kinase (ROCK) cascade and elevation of the NO/cyclic guanosine monophosphate (cGMP) level in cardiac tissue. In in vitro studies, cardiac fibroblast activation, proliferation, migration, and collagen production induced by Ang II were associated with activation of the G?12/13/RhoA/ROCK pathway, which was inhibited by exogenous 11,12-EET. Moreover, silencing of G?12/13 or RhoA exerted similar effects as 11,12-EET. Furthermore, inhibitory effects of 11,12-EET on G?12/13 were blocked by NO/cGMP pathway inhibitors. Our findings indicate that enhancement of the AA-CYP2J2-EET metabolic pathway by CYP2J2 overexpression attenuates Ang II-induced cardiac dysfunction and fibrosis by reducing the fibrotic response of cardiac fibroblasts by targeting the G?12/13/RhoA/ROCK pathway via NO/cGMP signaling.

| S-EPMC5496032 | biostudies-literature

Management of relapse in acute promyelocytic leukaemia treated with up-front arsenic trioxide-based regimens.

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| S-EPMC7894296 | biostudies-literature

CYP2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK?2 and enhancing nuclear translocation of Akt1.

Project description:Cytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5'-AMP-activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPK?2 and Akt1. Moreover, we tested whether EETs enhanced cross talk between AMPK?2 and phosphorylated Akt1 (p-Akt1), and stimulated nuclear translocation of p-Akt1, to exert their antihypertrophic effects. AMPK?2(-/-) mice that overexpressed CYP2J2 in heart were treated with Ang II for 2 weeks. Interestingly, overexpression of CYP2J2 suppressed cardiac hypertrophy and increased levels of atrial natriuretic peptide (ANP) in the heart tissue and plasma of wild-type mice but not AMPK?2(-/-) mice. The CYP2J2 metabolites, 11,12-EET, activated AMPK?2 to induce nuclear translocation of p-Akt1 selectively, which increased the production of ANP and therefore inhibited the development of cardiac hypertrophy. Furthermore, by co-immunoprecipitation analysis, we found that AMPK?2?2?1 and p-Akt1 interact through the direct binding of the AMPK?1 subunit to the Akt1 protein kinase domain. This interaction was enhanced by 11,12-EET. Our studies reveal a novel mechanism in which CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPK?2?2?1 and protect against cardiac hypertrophy and suggest that overexpression of CYP2J2 might have clinical potential to suppress cardiac hypertrophy and heart failure.

| S-EPMC5013012 | biostudies-literature

Inside epoxyeicosatrienoic acids and cardiovascular disease.

Project description:Epoxyeicosatrienoic acids (EETs) generated from arachidonic acid through cytochrome P450 (CYP) epoxygenases have many biological functions. Importantly, CYP epoxygenase-derived EETs are involved in the maintenance of cardiovascular homeostasis. In fact, in addition to their potent vasodilating effect, EETs have potent anti-inflammatory properties, inhibit platelet aggregation, promote fibrinolysis, and reduce vascular smooth muscle cell proliferation. All EETs are metabolized to the less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Numerous evidences support the role of altered EET biosynthesis in the pathophysiology of hypertension and suggest the utility of antihypertensive strategies that increase CYP-derived EET or EET analogs. Indeed, a number of studies have demonstrated that EET analogs and sEH inhibitors induce vasodilation, lower blood pressure and decrease inflammation. Some of these agents are currently under evaluation in clinical trials for treatment of hypertension and diabetes. However, the role of CYP epoxygenases and of the metabolites generated in cancer progression may limit the use of these drugs in humans.

| S-EPMC4226225 | biostudies-literature

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