Retinoic Acid Receptor β Expression and Growth Inhibition of Gynecologic Cancer Cells by the Synthetic Retinoid N-(4-Hydroxyphenyl) Retinamide

Sabichi, Anita L.; Hendricks, Denver T.; Bober, Mary A.; Birrer, Michael J.

doi:10.1093/jnci/90.8.597

Cited by 104 publications

(80 citation statements)

References 19 publications

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“…Data points show mean7S.D. of a representative experiment shown, 20 higher concentrations of 4HPR could inhibit growth in the majority of the ovarian cancer cell lines tested (data not shown). Treatment with 4HPR at 1 mM significantly enhances TRAIL-mediated growth inhibition in five of the nine ovarian cancer cell lines, but not in the immortalized nontumorigenic ovarian cell lines, IOSE 80 and IOSE 120 (Figure 1a).…”

Section: Hpr Enhances Trail-mediated Toxicity In Ovarian Cancer Cellsmentioning

confidence: 94%

“…18 In vitro studies in ovarian cancer cells have shown that 4HPR inhibits cell proliferation and induces apoptosis. 19,20 The mechanisms of action of 4HPR are not completely understood. Recent reports have indicated that 4HPR can induce apoptosis through RAR-dependent or -independent pathways.…”

Section: Introductionmentioning

confidence: 99%

“…Recent reports have indicated that 4HPR can induce apoptosis through RAR-dependent or -independent pathways. [20][21][22] The activation of the c-Jun N-terminal kinase, the activation of the mitochondrial pathway via generation of reactive oxygen species (ROS), or the induction of increased ceramide production have all been implicated in 4HPR-mediated apoptosis. 21,23,24 Recently, it was reported that 4HPR enhances the effect of chemotherapy in neuroblastoma and ovarian carcinomas.…”

Section: Introductionmentioning

confidence: 99%

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N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

et al. 2004

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The majority of ovarian cancer cells are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Subtoxic concentrations of the semisynthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) enhanced TRAIL-mediated apoptosis in ovarian cancer cell lines but not in immortalized nontumorigenic ovarian epithelial cells. The enhancement of TRAIL-mediated apoptosis by 4HPR was not due to changes in the levels of proteins known to modulate TRAIL sensitivity. The combination of 4HPR and TRAIL enhanced cleavage of multiple caspases in the death receptor pathway (including the two initiator caspases, caspase-8 and caspase-9). The 4HPR and TRAIL combination leads to mitochondrial permeability transition, significant increase in cytochrome c release, and increased caspase-9 activation. Caspase-9 may further activate caspase-8, generating an amplification loop. Stable overexpression of Bcl-xL abrogates the interaction between 4HPR and TRAIL at the mitochondrial level by blocking cytochrome c release. As a consequence, a decrease in activation of caspase-9, caspase-8, and TRAIL-mediated apoptosis occurs. These results indicate that the enhancement in TRAIL-mediated apoptosis induced by 4HPR is due to the increase in activation of multiple caspases involving an amplification loop via the mitochondrial-death pathway. These findings offer a promising and novel strategy for the treatment of ovarian cancer.

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Section: Hpr Enhances Trail-mediated Toxicity In Ovarian Cancer Cellsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

et al. 2004

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“…In vitro, HPR suppresses the growth of several tumor cell lines, including breast, ovarian and small cell lung carcinomas (Bhatnager et al, 1991;Kalemkerian et al, 1995;Sabichi et al, 1998), neuroblastomas (Mariotti et al, 1994), leukemias and lymphomas (Delia et al, 1993). In addition, HPR inhibits angiogenesis and endothelial cell motility (Pienta et al, 1996), and triggers apoptotic cell death (Delia et al, 1993(Delia et al, , 1995Mariotti et al, 1994;Pienta et al, 1996) through caspase activation (Piedra®ta and Pfahl, 1997).…”

Section: Introductionmentioning

confidence: 99%

pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

et al. 2000

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The cancer chemopreventive synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR) can inhibit the growth and induce apoptosis of tumor cells. In this study we analysed the growth suppressive e ect of HPR on human breast cancer cell lines in vitro and the role of the retinoblastoma protein (pRb) in this response. Treatment of MCF7, T47D and SKBR3 for 24 ± 48 h with 3 mM HPR, a concentration attainable in vivo, resulted in growth inhibition and marked dephosphorylation of pRb involving Ser 612 , Thr 821 , Ser 795 and Ser 780 , target residues for cyclin-dependent kinase 2 (Cdk2) the former two, and Cdk4 the latter two. Interestingly, this dephosphorylation of pRb occurred in S-G2-M phase cells, as revealed by experiments on cells fractionated by FACS according to the cell cycle phase, hence suggesting that the retinoid interferes with the regulation of pRb phosphorylation. The in vitro phosphorylation of a GST-pRb recombinant substrate by Cdk2 immunocomplexes from MCF7, T47D and SKBR3 was markedly suppressed after HPR treatment, whereas that by Cdk4 complexes was suppressed in T47D and SKBR3 but not in MCF7. The steady-state levels of Cdk2, Cdk4 and Cyclin A proteins were una ected by HPR, while those of Cyclin D1 were signi®cantly reduced in all three cell lines. Interestingly, Cyclin D1 downregulation by HPR correlated with transcriptional repression, but not with enhanced proteolysis of Cyclin D1 typically elicited by other retinoids. Collectively, our data suggest that the antiproliferative activity of HPR arises from its capacity to maintain pRb in a de-phosphorylated growthsuppressive status in S-G2/M, possibly through Cyclin D1 downregulation and inhibition of pRb-targeting Cdks.

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“…The growth inhibition was achieved at pharmacologically achievable concentrations for 8-ClcAMP (1 mM) and retinoic acid (1 nM). In a phase I clinical study of 8-Cl-cAMP, plasma concentrations of 8-Cl-cAMP as high as 4 mM were nontoxic (Tortora et al, 1995), and the synthetic retinoid, N-(4-hydroxylphenyl) retinamide (4HPR) produces growth inhibition at pharmacologically achievable concentrations of 1 ± 2 mM (Sabichi et al, 1998). This suggests feasibility of a combination treatment with 8-Cl-cAMP and a retinoic acid analog such as all-trans-RA.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of retinoic acid and 8-Cl-cAMP on apoptosis require caspase-3 activation in human ovarian cancer cells

Srivastava

Cho‐Chung

et al. 1999

Oncogene

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Retinoic Acid Receptor β Expression and Growth Inhibition of Gynecologic Cancer Cells by the Synthetic Retinoid N-(4-Hydroxyphenyl) Retinamide

Abstract: 4HPR inhibited the proliferation of ovarian cancer cells in vitro; RARbeta expression appeared to be associated with this effect.

Cited by 104 publications

References 19 publications

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines

pRb and Cdk regulation by N-(4-hydroxyphenyl)retinamide

Synergistic effects of retinoic acid and 8-Cl-cAMP on apoptosis require caspase-3 activation in human ovarian cancer cells

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