Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Zhang, Yuxiang; Dawson, Marcia I.; Ning, Yang‐Min; Polin, Lisa; Parchment, Ralph E.; Corbett, Thomas H.; Mohamed, Anwar N.; Feng, Kai; Farhana, Lulu; Rishi, Arun K.; Hogge, Donna E.; Leid, Mark; Peterson, Valerie J.; Zhang, Xiao Kun; Mohammad, Ramzi M.; Lu, Junyan; Willman, Cheryl L.; VanBuren, Eric; Biggar, Sandra; Edelstein, M; Eilender, David S.; Fontana, Joseph A.

doi:10.1182/blood-2003-01-0108

Cited by 26 publications

(54 citation statements)

References 70 publications

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“…It is likely that other protein factors and/or signal transduction pathways are also involved in the regulation of the Nur77-dependent apoptosis pathway. agreement with previous results (Zhang et al, , 2003Wan et al, 2001;Garattini et al, 2004;BoisvieuxUlrich et al, 2005), and they demonstrate that JNK activation is essential for the apoptotic effects of AHPN and its analogs.…”

Section: Discussionsupporting

confidence: 93%

“…They are known to activate JNK (Zhang et al, , 2003Wan et al, 2001;Garattini et al, 2004;Boisvieux-Ulrich et al, 2005), which is required for maximal apoptosis induction and precedes mitochondrial depolarization. Induction of apoptosis of breast and prostate cancer cells by AHPN is also associated with its inhibition of Akt activity (Farhana et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

et al. 2006

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Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN)/ CD437 class. In this study, we investigated the molecular mechanism by which AHPN/CD437 analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces Nur77 nuclear export. Our results demonstrate that 3-Cl-AHPC effectively activated Jun N-terminal kinase (JNK), which phosphorylates Nur77. Inhibition of JNK activation by a JNK inhibitor suppressed 3-Cl-AHPC-induced Nur77 nuclear export and apoptosis. In addition, several JNK upstream activators, including the phorbol ester TPA, anisomycin and MAPK kinase kinase-1 (MEKK1), phosphorylated Nur77 and induced its nuclear export. However, Nur77 phosphorylation by JNK, although essential, was not sufficient for inducing Nur77 nuclear export. Induction of Nur77 nuclear export by MEKK1 required a prolonged MEKK1 activation and was attenuated by Akt activation. Expression of constitutively active Akt prevented MEKK1-induced Nur77 nuclear export. Conversely, transfection of dominant-negative Akt or treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor accelerated MEKK1-induced Nur77 nuclear export. Furthermore, mutation of an Akt phosphorylation residue Ser351 in Nur77 abolished the effect of Akt or the PI3-K inhibitor. Together, our results demonstrate that both activation of JNK and inhibition of Akt play a role in translocation of Nur77 from the nucleus to the cytoplasm.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

et al. 2006

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“…3-Cl-AHPC was synthesized as described previously (20,21) and stored at À80jC in DMSO. DMEM-F12 medium, fetal bovine serum, Trizol reagent, and neomycin were purchased from Invitrogen, Inc. (Grand Island, NY).…”

Section: Methodsmentioning

confidence: 99%

“…We have previously shown that exposure of cells to 3-Cl-AHPC results in the cleavage of Bcl-X L and the generation of a proapoptotic molecule in leukemia cells (20,21). We investigated the effect of 3-Cl-AHPC on c-IAP1, c-IAP2, XIAP, and Bcl-X L in the MDA-MB-468 and DU145 cells.…”

Section: -[3-cl-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic Acidmentioning

confidence: 99%

“…We previously reported that exposure of cells to the novel compound 4-[3-Cl-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which binds to the retinoic acid receptor g (RARg) but does not activate it, results in apoptosis in cells in vitro as well as in an acute myelogenous leukemia mouse model with minimal toxicity (20,21). In addition, we found that exposure to 3-Cl-AHPC activated the expression of a number of genes that have NF-nB consensus sequences in their promoters.…”

Section: Introductionmentioning

confidence: 99%

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Apoptosis Induction by a Novel Retinoid-Related Molecule Requires Nuclear Factor-κB Activation

Farhana

Dawson²,

Fontana³

2005

Cancer Research

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Retinoids

Dawson¹

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retinoid drugs find major applications in the topical treatment of cutaneous proliferative disorders such as acne, psoriasis, and photoaging and cutaneous cancers such as cutaneous T‐cell lymphoma (CTCL) and Kaposi's sarcoma. Oral retinoids are successfully used to treat nodular/cystic acne, systemic CTCL, and acute promyelocytic leukemia. This overview of available retinoid drugs and those in the preclinical or clinical pipeline covers their development, indications, clinical trial results, adverse effects, and pharmacology/metabolism. Retinoids have been described historically and functionally in the context of interaction with their nuclear receptors—retinoic acid receptors (RARs) and retinoid X receptors (RXRs)—in inducing gene transcription. RAR‐selective retinoids or their prodrugs include first‐generation all‐ trans ‐retinoic acid (tretinoin) and its 13‐ cis isomer (isotretinoin), and second‐generation acitretin and its ethyl ester (etretinate), both having an aromatic 2,3,6‐trimethyl‐4‐methoxyphenyl terminus. Third‐generation more aromatic analogs include ethyl ester tazarotene (Tazorac®) and adapalene (Differin®), both selective for RAR subtypes β and γ, and RARα‐selective pipeline candidates Am80 and NRX 195183, which are in clinical trials. RAR and RXR transcriptional panagonist 9‐ cis ‐retinoic acid is next and is followed by RXR‐selective bexarotene (Targretin™) and two RXR‐selective clinical trial candidates, 9cUAB and NRX 194204. The fourth generation includes three compounds that may have applications in the treatment or prevention of cancer. While originally considered as retinoids, such as N ‐(4‐hydroxyphenyl) retinamide, or as retinoid‐related or derived, such as ST1926 (AHPC) and SHetA2, they subsequently were found to function independently of the RARs and RXRs in inhibiting cancer cell proliferation and inducing apoptosis.

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Induction of apoptosis in retinoid-refractory acute myelogenous leukemia by a novel AHPN analog

Cited by 26 publications

References 70 publications

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

Apoptosis Induction by a Novel Retinoid-Related Molecule Requires Nuclear Factor-κB Activation

Retinoids

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