An antagonist of retinoic acid receptors more effectively inhibits growth of human prostate cancer cells than normal prostate epithelium

Keedwell, Richard G.; Zhao, Yi; Hammond, Lisette; Kong, Wen; Qin, Suofu; Atangan, Larissa; Shurland, D-L; Wallace, David; Bird, Roger; Reitmair, Armin; Chandraratna, Roshantha A.S.; Brown, Geoffrey

doi:10.1038/sj.bjc.6602024

Cited by 24 publications

(33 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activation of RARγ favors cell proliferation and survival as opposed to differentiation [40]. As such, RARγ antagonists interfere with cell growth [41]. Here, RARα agonist AM580 or RARγ antagonist SR11253 had similar reductions in cell viability (Fig.…”

Section: Discussionmentioning

confidence: 96%

BCL-xL/MCL-1 inhibition and RARγ antagonism work cooperatively in human HL60 leukemia cells

Perri

Yap

et al. 2014

Experimental Cell Research

View full text Add to dashboard Cite

The acute promyelocytic leukemia (APL) subtype of acute myeloid leukemia (AML) is characterized by chromosomal translocations that result in fusion proteins, including the promyelocytic leukemia-retinoic acid receptor, alpha fusion protein (PML-RARα). All-trans retinoic acid (atRA) treatment is the standard drug treatment for APL yielding cure rates >80% by activating transcription and proteasomal degradation of retinoic acid receptor, alpha (RARα). Whereas combination therapy with As2O3 has increased survival further, patients that experience relapse and are refractory to atRA and/or As2O3 is a clinically significant problem. BCL-2 family proteins regulate apoptosis and over-expression of anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) family proteins has been associated with chemotherapeutic resistance in APL including impairment of the ability of atRA to induce growth arrest and differentiation. Here we investigated the novel BH3 domain mimetic, JY-1-106, which antagonizes the anti-apoptotic BCL-2 family members B-cell lymphoma-extra large (BCL-xL) and myeloid cell leukemia-1 (MCL-1) alone and in combination with retinoids including atRA, AM580 (RARα agonist), and SR11253 (RARγ antagonist). JY-1-106 reduced cell viability in HL-60 cells alone and in combination with retinoids. The combination of JY-1-106 and SR11253 had the greatest impact on cell viability by stimulating apoptosis. These studies indicate that dual BCL-xL/MCL-1 inhibitors and retinoids could work cooperatively in leukemia treatment.

show abstract

Section: Discussionmentioning

confidence: 96%

BCL-xL/MCL-1 inhibition and RARγ antagonism work cooperatively in human HL60 leukemia cells

Perri

Yap

et al. 2014

Experimental Cell Research

View full text Add to dashboard Cite

show abstract

“…For example, a RAR-a-specific antagonist LG100629 was shown to block essentially completely the induction of IGFBP3 and TGFB2 by RA in human bronchial epithelial cells (26), in contrast to our findings with pan-RAR modulator LG100815. On the other hand, several RAR antagonists, similarly to LG100815, were found to inhibit tumor cell growth (27)(28)(29)(30). It would be of interest to determine if these compounds act as LG100815-type RAR modulators.…”

Section: Discussionmentioning

confidence: 99%

Agonist and Antagonist of Retinoic Acid Receptors Cause Similar Changes in Gene Expression and Induce Senescence-like Growth Arrest in MCF-7 Breast Carcinoma Cells

et al. 2006

View full text Add to dashboard Cite

Biological effects of retinoids are mediated via retinoic acid (RA) receptors (RAR) and retinoid X receptors (RXR). The best-characterized mechanism of retinoid action is stimulation of transcription from promoters containing RA response elements (RARE). Retinoids induce senescence-like growth arrest in MCF-7 breast carcinoma cells; this effect is associated with the induction of several growth-inhibitory genes. We have now found that these genes are induced by RAR-specific but not by RXR-specific ligands. Genome-scale microarray analysis of gene expression was used to compare the effects of two pan-RAR ligands, one of which is a strong agonist of RARE-dependent transcription, whereas the other induces such transcription only weakly and antagonizes the inducing effect of RAR agonists. Both RAR ligands, however, produced very similar effects on gene expression in MCF-7 cells, suggesting that RARE-dependent transcription is only a minor component of retinoid-induced changes in gene expression. The effects of RAR ligands on gene expression parallel changes associated with damage-induced senescence, and both ligands induced G 1 arrest and the senescent phenotype in MCF-7 cells. The RAR ligands up-regulated many tumor-suppressive genes and down-regulated multiple genes with oncogenic activities. Genes that are strongly induced by RAR ligands encode secreted bioactive proteins, including several tumor-suppressing factors. In agreement with these observations, retinoid-treated MCF-7 cells inhibited the growth of retinoid-insensitive MDA-MB-231 breast carcinoma cells in coculture. These results indicate that RARE-independent transcriptional effects of RAR ligands lead to senescence-like growth arrest and paracrine growthinhibitory activity in MCF-7 breast carcinoma cells. (Cancer Res 2006; 66(17): 8749-61)

show abstract

“…It is important to mention that the mechanism(s) of action of these synthetic retinoid-related molecules does not appear to involve retinoid receptors. Keedwell et al [74] showed that a retinoid-related molecule, which neither binds effectively to RARs and RXRs nor transactivates in RAR-and RXRmediated reporter assays, rapidly induced apoptosis in primary cultures from PCa, thus opening a new field of studies about non-classical actions of retinoids. On the other hand, studies showed that synthetic retinoids antagonizing RARs are potent growth inhibitors of PCa cell lines [45].…”

Section: Retinoids and Prostate Cancermentioning

confidence: 98%

“…On the other hand, studies showed that synthetic retinoids antagonizing RARs are potent growth inhibitors of PCa cell lines [45]. Keedwell et al [74] showed that 5 days of exposure to a high-affinity pan-RAR antagonist (AGN194310) abolished growth of PCa cells from 14 out of 14 patients, with half-maximal inhibition between 200 and 800 nM; it had similar effects (at approximately 250 nM) on the PCa lines LNCaP, DU-145, and PC-3. AGN194310 inhibited the growth of normal prostate epithelium cells less potently, by 50% at approximately 1 uM.…”

Section: Retinoids and Prostate Cancermentioning

confidence: 99%

Natural and Synthetic Retinoids in Prostate Cancer

Pasquali¹,

Rossi²,

Bellastella³

et al. 2006

CPD

View full text Add to dashboard Cite

Prostate cancer (PCa) is the most common cancer for men in Europe, North America, and some parts of Africa. Initially, growth of prostate cancer is usually androgen-dependent, but often it becomes androgen-independent after androgen-deprivation therapy. Managing hormone-refractory prostate carcinoma remains a difficult challenge for clinicians. Retinoids, vitamin A and its synthetic analogs are one of the most studied class of chemopreventive drugs for PCa. Retinoids play a key role in several vital functions as vision and development, and also exert anti-proliferative actions. Anti-proliferative effects of retinoids rely on the regulation of many biological processes, including differentiation, cell proliferation, and apoptosis. Retinoid actions are mediated by two classes of nuclear proteins called retinoic acid (RARalpha,beta and gamma and retinoic alpha,beta and gamma receptors, which are ligand-regulated transcription factors. Effects of both all-trans-retinoic acid (RA), the natural active derivative of vitamin A, and its synthetic derivatives, on prostate gland or prostate cell lines implicate retinoids in the regulation of prostate growth and suppression of PCa development. Deficient retinoid availability and action at the cellular level because of either decreased content or altered metabolism in PCa cells can play a key role in abnormal cellular differentiation pathways, and the loss of anti-proliferative effects. Here we review the in vitro and in vivo effects of retinoids in PCa.

show abstract

An antagonist of retinoic acid receptors more effectively inhibits growth of human prostate cancer cells than normal prostate epithelium

Cited by 24 publications

References 46 publications

BCL-xL/MCL-1 inhibition and RARγ antagonism work cooperatively in human HL60 leukemia cells

BCL-xL/MCL-1 inhibition and RARγ antagonism work cooperatively in human HL60 leukemia cells

Agonist and Antagonist of Retinoic Acid Receptors Cause Similar Changes in Gene Expression and Induce Senescence-like Growth Arrest in MCF-7 Breast Carcinoma Cells

Natural and Synthetic Retinoids in Prostate Cancer

Contact Info

Product

Resources

About