JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells

Davison, Kelly; Mann, Koren K.; Waxman, Samuel; Miller, Wilson H.

doi:10.1182/blood-2003-05-1412

Cited by 139 publications

(123 citation statements)

References 34 publications

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“…[29][30][31] Davison et al also suggested that activation of the JNK pathway correlates with reversal of drug resistance by showing a temporal association of L-buthionine-[S,R]-sulfoximine treatment, JNK activation and sensitization of arsenic trioxide-resistant NB4 acute promyelocytic leukemia sublines to arsenic. 32 We evaluated our in vitro results in bone marrow cells obtained from AML patients before chemotherapy and confirmed the hypothesis that chemoresistance may be attributed to failure of JNK activation. We monitored the dynamic changes of phospho-JNK levels of primary leukemic cells after their in vitro exposure to anthracyclines.…”

Section: Discussionsupporting

confidence: 62%

c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia

et al. 2008

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Section: Discussionsupporting

confidence: 62%

c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia

et al. 2008

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“…1C), so 5 M of arsenite treatment was used as a negative control in the following studies. It may be noticed that the cytotoxicity of arsenite to cells is dependent on the forms of arsenite used (25,26) and cell types as well as species (27,28). For example, the cytotoxicity as well as cellular biological effects of arsenic trioxide and sodium arsenite are quite different when they are compared at the same concentration, which has been observed from the findings of various laboratories (5,10).…”

Section: Resultsmentioning

confidence: 58%

Coordination of JNK1 and JNK2 Is Critical for GADD45α Induction and Its Mediated Cell Apoptosis in Arsenite Responses

Zhang

Song

et al. 2006

Journal of Biological Chemistry

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Arsenite is a well documented environmental pathogen, whereas it has also been applied as medication to treat various neoplasmas. The pathogenic and therapeutic effects of arsenite are associated with cellular apoptotic responses. However, the molecular mechanisms of arsenite-induced apoptosis are not very well understood. Our previous study has shown that arsenite exposure is able to activate JNKs, which subsequently mediate the apoptotic outcome. The present study further revealed that the coordination of JNK1 and JNK2 was critical for the arsenite-induced expression of GADD45␣ (growth arrest and DNA damage 45␣), which in turn mediated the cellular apoptosis. The arsenite-induced apoptosis and GADD45␣ expression were significantly impaired in mouse embryonic fibroblasts deficient in either jnk1 (JNK1 ؊/؊ ) or jnk2 (JNK2 ؊/؊ ). Knockdown of GADD45␣ by its specific small interfering RNA also dramatically reduced the apoptotic responses, and overexpression of GADD45␣ in either JNK1 ؊/؊ or JNK2 ؊/؊ mouse embryonic fibroblasts partially resensitized the cell death. Furthermore, it was found that the regulation of GADD45␣ by JNK1 and JNK2 was achieved through mediating the activation of c-Jun, since in the JNK1 ؊/؊ and JNK2 ؊/؊ cells the c-Jun activation was impaired, and overexpression of the dominant negative mutant of c-Jun (TAM67) in wild type cells could also block GADD45␣ induction as well as cellular apoptosis. Our results demonstrate that the coordination of JNK1 and JNK2 is critical for c-Jun/ GADD45␣-mediated cellular apoptosis induced by arsenite.Arsenite occurs naturally in the earth's crust and is widely distributed in the environment (1). Human exposure to arsenite occurs mainly by ingestion of drinking water contaminated with arsenite from naturally occurring sources or through the inhalation of contaminated dusts in occupational settings (2). As an environmental pathogen, arsenite causes a series of pathophysiological alterations, including immunosuppression and carcinogenesis (3). Paradoxically, arsenite has also been applied as chemotherapeutic reagents to treat various neoplasmas (4). Further insights into the pathogenic and therapeutic effects of arsenite show that it seems to be associated with the apoptotic induction in both normal and tumor cells (5, 6). The inhibition of antiapoptotic Bcl-2 and activation of proapoptotic mitogen-activated protein kinases has recently been shown to participate in the arsenite-induced apoptotic process in various cell models (7-12). These observations suggest that the alternation of the cascades of cellular survival/proapoptotic signaling pathways may be critical for cell apoptotic responses triggered by arsenite. However, the detailed molecular mechanisms still remain to be elucidated.In this study, we applied wild type (WT), 2 JNK1 Ϫ/Ϫ , and JNK2 Ϫ/Ϫ , three immortalized mouse embryonic fibroblasts (MEFs) to evaluate the roles of JNK1 and JNK2 in arseniteinduced apoptosis. It was found that the arsenite-induced apoptosis required both JNK1 and JNK2, since the...

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“…15 Therefore, we asked whether the activation of JNK might play a role in darinaparsin-mediated apoptosis in NB4 cells. First, we assessed JNK activation using an immune complex assay with GST-c-jun as an exogenous substrate.…”

Section: Jnk Activation Mediates Apoptosis Induced By Both As 2 O 3 Amentioning

confidence: 99%

“…Using pharmacologic and genetic approaches, we and others demonstrated that c-Jun NH 2 -terminal kinase (JNK) activation is required for As 2 O 3 -induced apoptosis in several malignant cell lines, including the APL cell line NB4. 14,15 As 2 O 3 has been investigated in the treatment of non-APL malignancies. 16,17,18 However, most of these studies showed substantially reduced antitumor effects of clinically achievable levels of As 2 O 3 , compared with those seen in APL.…”

Section: Introductionmentioning

confidence: 99%

A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines

et al. 2008

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Inorganic arsenic trioxide (As 2 O 3 ) is a highly effective treatment for acute promyelocytic leukemia (APL). However, other cancers do not respond well to this form of arsenic at clinically achievable doses. We tested a novel arsenical, S-dimethylarsino-glutathione (darinaparsin) for efficacy in various malignancies in vitro. Darinaparsin is significantly more potent than As 2 O 3 at mediating apoptosis in various malignant cell lines and is highly active against APL cells derived for As 2 O 3 resistance. We provide evidence that darinaparsin triggers apoptosis by inducing signaling pathways that do not completely overlap with As 2 O 3 . We show that darinaparsin induces apoptosis and oxidative stress to a greater extent than As 2 O 3 , although like As 2 O 3 , darinaparsin-induced toxicity is c-Jun NH 2 -terminal kinase-dependent. However, darinaparsin does not induce promyelocytic leukemia/retinoic acid receptor a (PML/ RARa) degradation or rearrange PML nuclear bodies in APL cells, nor is its toxicity increased by glutathione depletion. Darinaparsin treatment results in higher intracellular arsenic accumulation when compared to As 2 O 3 treatment. This may be explained by our finding that As 2 O 3 , but not darinaparsin, is efficiently exported by ABCC1, suggesting increased therapeutic efficacy of darinaparsin in ABCC1-overexpressing tumors. Our studies indicate that darinaparsin efficiently kills tumor cells with increased antioxidant capacity and drug exporters and suggest that darinaparsin may have a broader therapeutic spectrum than As 2 O 3 .

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JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells

Cited by 139 publications

References 34 publications

c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia

c-Jun N-terminal kinase activation failure is a new mechanism of anthracycline resistance in acute myeloid leukemia

Coordination of JNK1 and JNK2 Is Critical for GADD45α Induction and Its Mediated Cell Apoptosis in Arsenite Responses

A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines

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