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Old 06-29-2009, 01:32 AM   #1
Rich66
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Targretin: Vitamin-A Derivative Provides Clues To Better Breast Cancer Drugs

(Retinoic acid, relationship to ER, telomerase inhib, helpful in triple neg, Bexarotene, HDAC inhib, induces differentiation, CSC, resistance reversal, not w/etoposide, RA syndrome)



Vitamin-A Derivative Provides Clues To Better Breast Cancer Drugs


26 Jun 2009

Retinoic acid, a derivative of vitamin A, could lead researchers to a new set of drug targets for treating breast cancer, researchers from the University of Chicago report in the June 25, 2009, issue of the journal Cell.

The most common forms of breast cancer are fueled by the female hormone estrogen. By comparing the effects of estrogen and retinoic acid on the entire genome, the researchers found that they have a "yin-yang" effect. They alter the expression of many of the same genes, with estrogen tipping the scales towards cell proliferation and retinoic acid restoring the balance by inhibiting cellular growth.

This balanced control of gene expression regulates fundamental cellular processes, say the authors. When it is dysregulated, it can lead to cancer.

"Understanding all the components of this process could be used against breast cancer care in three ways," said study leader, Kevin White, PhD, professor of human genetics and director of the Institute for Genomics and System Biology at the University of Chicago. "It suggests new ways to think about preventing the disease in those at high risk. It offers molecular tools that could provide a more precise diagnosis and predict outcomes. It could also be used to enhance current therapies, making existing drugs, such as tamoxifen, that selectively block estrogen's effects even more powerful, or even to develop new anti-cancer drugs."

White's team studies the effects of nuclear receptors, a class of proteins found within cells that control the response to various hormones. When a hormone enters a cell and connects with its receptor, that receptor alters the pattern of expression of specific genes--often hundreds or more.

For this study, White and colleagues Sujun Hua and Ralf Kittler focused on the retinoic acid receptors. Retinoic acid, known for its anticancer effects and already in use to treat a rare form of leukemia, has also been associated with anti-proliferative changes in breast cancer cells.

So the team combined two laboratory techniques--a process known as "ChIP-chip analysis" that blends chromatin immunoprecipitation (ChIP), to see where the retinoic acid receptors bound to the genome, with micro-array gene-chip analysis, to measure expression levels of specific genes.

The combination enabled them to map out all the genetic effects of retinoic acid and its receptors in a cell line derived from patients with breast cancers that were fueled by estrogen.

They found that 39 percent of the genomic regions bound by estrogen receptor alpha overlapped with those bound by retinoic acid. They also found that the binding of estrogen and retinoic acids receptors to target sites were often mutually exclusive. This means the two hormones compete to activate or repress many of the same genes.

The two signaling pathways were mainly antagonistic. Estrogen increased expression of 139 genes that retinoic repressed. Retinoic acid activated 185 genes that estrogen repressed. For about 140 genes, estrogen and retinoic acid had the same effect.

"Collectively, note the authors, "these findings indicate an extensive crosstalk" between the effects of estrogen and retinoic acid. Despite their opposing effects, certain versions of the estrogen and retinoic acid receptors actually activate each other. This provides "an additional level of control," say the authors, "for achieving a balanced regulation of gene expression."

This competition between the two signals also provides a new tool to predict outcomes. The researchers compared the effects of retinoic acid on tissues from 295 breast cancer patients against the results from their initial study using a typical breast cancer cell line. They found that the more responsive a tumor was to retinoic acid, the better the odds of long-term relapse-free survival.

Some of the genes that respond to retinoic acid were expressed even in difficult-to-treat tumors, such as those that do not have estrogen receptors or the molecule targeted by the drug Herceptin, the so-called double- or triple-negative breast cancers. "Some of these genes may provide new drug targets," White said.

Although retinoic acid is approved for treatment of leukemia, it can be quite toxic and patients can develop resistance to the drug. This study suggests a long series of downstream targets that are activated by the RA receptor.

"The goal would be to develop drugs that could activate these cancer-inhibiting targets," said White. "Retinoic acid itself is probably not the solution because of its side effects and metabolic byproducts," He cautioned, "but our results provide a molecular justification for finding ways to overcome its limitations in the clinic."

"This work reveals important insights on the interplay between vitamin A and estrogen action," said Myles Brown, MD, professor of medicine at Harvard Medical School and the Dana Farber Cancer Institute. "These insights will hopefully lead to new approaches for the prevention and treatment of the most common form of breast cancer."

The National Institutes of Health and a grant from the Chicago Biomedical Consortium (CBC) with support from the Searle Funds at the Chicago Community Trust funded the research.

Source: University of Chicago Medical Center


1: Cancer Chemother Pharmacol. 2009 Sep 24. [Epub ahead of print] Links
Bexarotene: a promising anticancer agent.

Qu L, Tang X.
Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, 388 Yuhang Tang Road, 310058, Hangzhou, Zhejiang, People's Republic of China.
Retinoids are biologically active derivatives of vitamin A, which play essential roles in embryonic or adult cell behavior modulating cell proliferation, differentiation and apoptosis. The biologic effects of retinoids are mediated by two distinct families of intracellular receptors: retinoid acid receptors (RARs)-alpha, -beta and -gamma and retinoid X receptors (RXR)-alpha, -beta and -gamma. Bexarotene is a selective RXR agonist, which exerts its effects in blocking cell cycle progression, inducing apoptosis and differentiation, preventing multidrug resistance, and inhibiting angiogenesis and metastasis, making it a promising chemopreventive agent against cancer.
PMID: 19777233 [PubMed - as supplied by publisher

Current website:

http://www.targretin.com/



1: Cell Mol Life Sci. 2004 Jun;61(12):1475-84. Links
How retinoids regulate breast cancer cell proliferation and apoptosis.

Simeone AM, Tari AM.
Department of Bioimmunotherapy, Section of Immunobiology and Drug Carriers, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas, USA.
Breast cancer still remains a major problem in its incidence, morbidity and mortality; therefore, more effective strategies for its prevention are urgently needed. Retinoids, natural and synthetic derivatives of vitamin A, possess antiproliferative and proapoptotic properties, making them a promising class of chemopreventive agents against breast cancer. The efficacy of all-trans retinoic acid, 9-cis-retinoic acid, LGD1069 (Targretin, bexarotene), and N-(4-hydroxyphenyl)retinamide (fenretinide) as breast cancer chemopreventive agents is being studied. A better understanding of the molecular mechanisms of action of these agents should lead to improvements in their clinical application. In this review, we discuss the mechanisms by which retinoids exert their antiproliferative and apoptotic effects in breast cancer cells.
PMID: 15197471 [

Anticancer Res. 2009 Dec;29(12):4959-4964.
Retinoid-induced Histone Deacetylation Inhibits Telomerase Activity in Estrogen Receptor-negative Breast Cancer Cells.

Phipps SM, Love WK, White T, Andrews LG, Tollefsbol TO.
Department of Biology, 175 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294-1170, U.S.A. trygve@uab.edu.
BACKGROUND: Multiple mechanisms regulate cancer-associated telomerase activity at the level of human telomerase reverse transcriptase (hTERT) transcription which may serve as novel targets for anticancer approaches. MATERIALS AND METHODS: The effects of prolonged all-trans retinoic acid (ATRA) exposure on hTERT regulation in estrogen receptor-negative SK-BR-3 breast cancer cells were examined. RESULTS: ATRA had a profound effect on the morphology and proliferation rate of the SK-BR-3 cells. ATRA also hindered the ability of these cancer cells to grow independently, rendering them more like normal somatic cells. The effect of ATRA on the decrease of telomerase activity was found to be associated with a rapid decrease in histone H3-lysine 9 acetylation (H3-K9-Ac) of the hTERT promoter. Extended-exposure to ATRA in these cells also caused the initiation of a putative compensatory mechanism, counteracting the induced surge in apoptosis. CONCLUSION: A rapid decrease of H3-K9 acetylation at the hTERT promoter could be an important mechanism by which ATRA shuts down telomerase activity and mediates its antitumor effects in estrogen receptor-negative breast cancer cells.

PMID: 20044602 [PubMed - as supplied by publisher]



1: Cancer Prev Res (Phila Pa). 2008 Aug;1(3):208-14. Links
Combination chemoprevention of HER2/neu-induced breast cancer using a cyclooxygenase-2 inhibitor and a retinoid X receptor-selective retinoid.

Brown PH, Subbaramaiah K, Salmon AP, Baker R, Newman RA, Yang P, Zhou XK, Bissonnette RP, Dannenberg AJ, Howe LR.
Breast Center, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
The inducible prostaglandin synthase isoform cyclooxygenase-2 (COX-2) is overexpressed in approximately 40% of human breast carcinomas and in precancerous breast lesions, particularly in association with overexpression of human epidermal growth factor receptor 2 (HER2/neu). Experimental breast cancer can be suppressed by pharmacologic inhibition or genetic ablation of Cox-2, suggesting potential clinical utility of COX-2 inhibitors with respect to breast cancer. Importantly, several clinical trials have found reduced colorectal adenoma formation in individuals administered selective COX-2 inhibitors. However, such trials also identified increased cardiovascular risk associated with COX-2 inhibitor use. The goal of this research was to test whether improved chemopreventive efficacy could be achieved by combining submaximal doses of a selective COX-2 inhibitor and a retinoid X receptor-selective retinoid (rexinoid). The rate of HER2/neu-induced mammary tumor formation was substantially delayed by coadministration of the COX-2 inhibitor celecoxib (500 ppm in diet) and the rexinoid LGD1069 (10 mg/kg body weight; oral gavage) to MMTV/neu mice. Median time to tumor formation was increased from 304 to >600 days (P < 0.0001). The combination was substantially more effective than either drug individually. Similarly, potent suppression of aromatase activity was observed in mammary tissues from the combination cohort (44% of control; P < 0.001). Regulation of aromatase expression and activity by COX-derived prostaglandins is well established. Interestingly however, single agent LGD1069 significantly reduced mammary aromatase activity (71% of control; P < 0.001) without modulating eicosanoid levels. Our data show that simultaneous blockade of COX/prostaglandin signaling and retinoid X receptor-dependent transcription confers potent anticancer efficacy, suggesting a novel avenue for clinical evaluation.
PMID: 19138958 [PubMed - indexed for MEDLINE


1: Mol Cancer Ther. 2005 May;4(5):824-34. Links
The selective retinoid X receptor agonist bexarotene (LGD1069, Targretin) prevents and overcomes multidrug resistance in advanced breast carcinoma.

Yen WC, Lamph WW.
Department of Molecular Oncology, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, CA 92121, USA.
Acquired drug resistance represents a major challenge in the therapeutic management of breast cancer patients. We reported previously that the retinoid X receptor-selective agonist bexarotene (LGD1069, Targretin) was efficacious in treating animal models of tamoxifen-resistant breast cancer. The goal of this study was to evaluate the effect of bexarotene on development of acquired drug resistance and its role in overcoming acquired drug resistance in advanced breast cancer. Paclitaxel, doxorubicin, and cisplatin were chosen as model compounds to determine the effect of bexarotene on the development of acquired drug resistance. Human breast cancer cells MDA-MB-231 were repeatedly treated in culture with a given therapeutic agent with or without bexarotene for 3 months. Thereafter, cells were isolated and characterized for their drug sensitivity. Compared with parental cells, cells treated with a single therapeutic agent became resistant to the therapeutic agent, whereas cells treated with the bexarotene combination remained chemosensitive. Cells with acquired drug resistance, when treated with the combination, showed increased sensitivity to the cytotoxic agent. Furthermore, cells treated with the combination regimen had reduced invasiveness and angiogenic potential than their resistant counterparts. These in vitro findings were further confirmed in an in vivo MDA-MB-231 xenograft model. Our results suggest a role for bexarotene in combination with chemotherapeutic agents in prevention and overcoming acquired drug resistance in advanced breast carcinoma.
PMID: 15897247 [PubMed - indexed for MEDLINE





J Endocrinol. 2004 Nov;183(2):395-404.
All trans-retinoic acid acts synergistically with hydroxytamoxifen and transforming-growth factor beta to stimulate apoptosis in MCF-7 breast cancer cells.

Danforth DN Jr.
Surgery Branch, National Cancer Institute, National Institutes of Health, Bldg. 10/Rm 2B42, Bethesda, Maryland 20892, USA. David_Danforth@nih.gov
The anti-estrogen 4-hydroxytamoxifen (TAM) and vitamin A-related compounds, the retinoids, in combination act synergistically to inhibit growth of breast cancer cells in vitro and in vivo. To clarify the mechanism of this synergism, the effect of TAM and all trans-retinoic acid (AT) on proliferation of MCF-7 breast cancer cells was studied in vitro. TAM and AT acted synergistically to cause a time-dependent and dose-dependent inhibition of MCF-7 cell growth. In a temporally related manner, TAM+AT acted synergistically to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis. TAM and AT each blocked cell cycle progression throughout 7 days of treatment but without any synergistic or additive effect on this process, indicating a selective synergism for apoptosis. The negative growth factor-transforming growth factor beta (TGFbeta) is secreted by these cells and was studied as a potential mediator of the synergistic effects of TAM+AT on apoptosis. TAM+AT acted synergistically to induce a fivefold increase in TGFbeta1 secretion over 72 h. TGFbeta1 alone had no apoptotic effects on these cells; however, TGFbeta1 in combination with AT acted synergistically to inhibit growth, to downregulate Bcl-2 mRNA and Bcl-2 protein expression, and to stimulate apoptosis of these cells in a manner comparable with that noted for TAM+AT. The synergism of both TAM+AT and TGFbeta1+AT for apoptosis was suppressed by estradiol. Co-incubation of TAM+AT with anti-TGFbeta antibody did not block down-regulation of Bcl-2 protein expression or stimulation of apoptosis. The synergistic effects of TAM+AT on apoptosis therefore occur independently of TGFbeta, although TGFbeta may interact with AT in a novel manner to provide another important anti-proliferative mechanism for breast cancer cells.

PMID: 15531727 [PubMed - indexed for MEDLINE]







http://breast-cancer-research.com/content/10/4/210

Breast cancer stem cells as therapeutic targets

In the past two decades, more than 30 new anticancer drugs have been introduced, but survival rates have improved only marginally for many forms of cancer [65]. In contrast to most cancer cells, cancer stem cells are slow-dividing and have a lowered ability to undergo apoptosis and a higher ability of DNA repair, making them more resistant to traditional methods of cancer treatment such as radiation and chemotherapy. In vitro experiments comparing differentiated breast cancer cells grown under monolayer conditions with CD24-/low CD44+ cancer stem cells grown under mammosphere conditions showed that the stem cell-like population was more resistant to radiation [66]. In addition, stem cells express ABC drug transporters, which protect the cell from cytotoxic agents and may lead to MDR [67]. Current anti-cancer therapy is effective at debulking the tumour mass but treatment effects are transient, with tumour relapse and metastatic disease often occurring as a result of the failure of targeting cancer stem cells. For therapy to be more effective, debulking of differentiated tumours must occur followed by targeting of the remaining surviving, often quiescent, tumour stem cells. This could be accomplished by differentiating BCSCs through differentiating therapy or eliminating them via immunotherapy.
Differentiation therapy targeting cancer stem cells

One way to target cancer stem cells is to induce the cancer stem cells to differentiate. Targeting the cancer stem cell pool to differentiate results in the loss of the ability for self-renewal, a hallmark of the cancer stem cell phenotype and the reason behind maintenance of the cancer stem cells. One differentiation agent used in the clinic is retinoic acid (RA) (vitamin A) [68]. RA and vitamin A analogues can promote differentiation of epithelial cells and reverse tumour progression through modulation of signal transduction. RA-based therapy followed by chemotherapy has found use in acute promyeloctyic leukaemia and could also find use in solid tumour therapy [69]. Recently, the use of bone morpho-genetic protein (BMP)-4 has been described as a non-cytotoxic effector capable of blocking the tumourigenic potential of human glioblastoma cells [70]. This therapeutic agent is able to work by reducing proliferation and inducing expression of neural differentiation markers in stem-like tumour-initiating precursors. These findings are intriguing in light of the role that BMP-4 may play in some breast tumours [71]. Finding ways to specifically target BCSCs via differentiation therapy is an application that needs to be further defined.




1: Cancer Lett. 2009 Jun 9. [Epub ahead of print] Links
Acyclic retinoid synergises with valproic acid to inhibit growth in human hepatocellular carcinoma cells.

Tatebe H, Shimizu M, Shirakami Y, Sakai H, Yasuda Y, Tsurumi H, Moriwaki H.
Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
A malfunction of retinoid X receptor-alpha (RXRalpha) due to phosphorylation is associated with the development of hepatocellular carcinoma (HCC) and acyclic retinoid (ACR), which targets RXRalpha, can prevent the development of second primary HCC. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, induces apoptosis and cell cycle arrest in cancer cells. VPA can also enhance the sensitivity of cancer cells to retinoids. The present study examined the possible combined effects of ACR plus VPA in HepG2 human HCC cell line. The combination of 5muM ACR and 1mM VPA, about the IC(25) value for both compounds, synergistically inhibited the growth of HepG2 cells without affecting the growth of Hc normal human hepatocytes. The combined treatment with ACR plus VPA also acted synergistically to induce apoptosis and G(0)-G(1) cell cycle arrest in HepG2 cells. This combination further exerted a synergistic inhibition of the phosphorylation of RXRalpha, ERK, Akt and GSK-3beta proteins and caused an accumulation of acetylated histones H3 and H4 proteins. VPA enhanced the ability of ACR to raise the cellular levels of RARbeta and p21(CIP1). The combination of these agents markedly increased both the RARE and RXRE promoter activities in HepG2 cells. These results suggest that ACR and VPA cooperatively increase the expression of RARbeta and p21(CIP1), while inhibiting the phosphorylation of RXRalpha, and these effects were associated with induction of apoptosis and the inhibition of cell growth in HepG2 cells. This combination might therefore be an effective regimen for the chemoprevention and chemotherapy of HCC.
PMID: 19520494 [P




1: Cell Cycle. 2009 Oct 15;8(20):3297-302. Epub 2009 Oct 10. Links
Retinoid signaling regulates breast cancer stem cell differentiation.

Ginestier C, Wicinski J, Cervera N, Monville F, Finetti P, Bertucci F, Wicha MS, Birnbaum D, Charafe-Jauffret E.
Centre de Recherche en Cancérologie de Marseille, UMR891 Inserm/Institut Paoli-Calmettes, Marseilles, France. christophe.ginestier@inserm.fr
The cancer stem cell (CSC) hypothesis implicates the development of new therapeutic approaches to target the CSC population. Characterization of the pathways that regulate CSCs activity will facilitate the development of targeted therapies. We recently reported that the enzymatic activity of ALDH1, as measured by the ALDELFUOR assay, can be utilized to isolate normal and malignant breast stem cells in both primary tumors and cell lines. In this study, utilizing a tumorsphere assay, we have demonstrated the role of retinoid signaling in the regulation of breast CSCs self-renewal and differentiation. Utilizing the gene set enrichment analysis (GSEA) algorithm we identified gene sets and pathways associated with retinoid signaling. These pathways regulate breast CSCs biology and their inhibition may provide novel therapeutic approaches to target breast CSCs.
PMID: 19806016 [PubMed - in process



Retinoic acid syndrome: A syndrome that occurs from treatment with retinoic acid and is characterized by fever, dyspnea (difficulty breathing), chest pain, lung infiltrates evident on chest X-ray, pleural and pericardial effusions (fluid around the lungs and heart) and hypoxia (lack of oxygen). The syndrome occurs within the first 3 weeks of retinoic acid treatment, for example, with the drug ATRA (all-trans retinoic acid) used in treating APL acute promyelocytic leukemia).
The retinoic acid syndrome involves the adhesion (sticking) of malignant cells in the pulmonary blood vessels. Steroids, chemotherapy, and supportive measures can help. The syndrome is a very serious complication. About 10% of patients with the syndrome die of it.







Mol Cancer. 2010 Jan 26;9:15.
Retinoic acid protects human breast cancer cells against etoposide-induced apoptosis by NF-kappaB-dependent but cIAP2-independent mechanisms.

Jiménez-Lara AM, Aranda A, Gronemeyer H.
Instituto de Investigaciones Biomédicas de Madrid Alberto Sols, CSIC/UAM, Madrid, Spain. amjimenez@iib.uam.es

FREE TEXT

Abstract

BACKGROUND: Retinoids, through their cognate nuclear receptors, exert potent effects on cell growth, differentiation and apoptosis, and have significant promise for cancer therapy and chemoprevention. These ligands can determine the ultimate fate of target cells by stimulating or repressing gene expression directly, or indirectly through crosstalking with other signal transducers. RESULTS: Using different breast cancer cell models, we show here that depending on the cellular context retinoids can signal either towards cell death or cell survival. Indeed, retinoids can induce the expression of pro-apoptotic (i.e. TRAIL, TNF-Related Apoptosis-Inducing Ligand, Apo2L/TNFSF10) and anti-apoptotic (i.e. cIAP2, inhibitor of apoptosis protein-2) genes. Promoter mapping, gel retardation and chromatin immunoprecipitation assays revealed that retinoids induce the expression of this gene mainly through crosstalk with NF-kappaB. Supporting this crosstalk, the activation of NF-kappaB by retinoids in T47D cells antagonizes the apoptosis triggered by the chemotherapeutic drugs etoposide, camptothecin or doxorubicin. Notably apoptosis induced by death ligands (i.e. TRAIL or antiFAS) is not antagonized by retinoids. That knockdown of cIAP2 expression by small interfering RNA does not alter the inhibition of etoposide-induced apoptosis by retinoids in T47D cells reveals that stimulation of cIAP2 expression is not the cause of their anti-apoptotic action. However, ectopic overexpression of a NF-kappaB repressor increases apoptosis by retinoids moderately and abrogates almost completely the retinoid-dependent inhibition of etoposide-induced apoptosis. Our data exclude cIAP2 and suggest that retinoids target other regulator(s) of the NF-kappaB signaling pathway to induce resistance to etoposide on certain breast cancer cells. CONCLUSIONS: This study shows an important role for the NF-kappaB pathway in retinoic acid signaling and retinoic acid-mediated resistance to cancer therapy-mediated apoptosis in breast cancer cells, independently of cIAP2. Our data support the use of NF-kappaB pathway activation as a marker for screening that will help to develop novel retinoids, or retinoid-based combination therapies with improved efficacy.

PMID: 20102612 [PubMed - indexed for MEDLINE]PMCID: PMC2825243Free PMC Article


Anticancer Res. 2009 Aug;29(8):2899-904.
Loss of anti-proliferative effect of all-trans retinoic acid in advanced stage of breast carcinogenesis.

Ahn EH, Chang CC, Talmage DA.
Department of Food and Nutrition, Chung-Ang University, Anseong-si, Gyeonggi-do, South Korea.
Abstract

BACKGROUND: Mechanisms by which the inhibitory effect of retinoic acid on tumor growth is attenuated as tumors progress to more advanced stages are unclear. MATERIALS AND METHODS: This study utilizes a novel cell culture system of human breast epithelial cells (HBEC). Immortal (M13SV1), weakly tumorigenic (M13SV1-R2), and highly tumorigenic (M13SV1-R2N1) transformed Type I HBEC were derived sequentially from the same parental Type I HBEC (stem cells) developed from reduction mammoplasty of healthy women. Effects of all-trans retinoic acid (AT-RA) on the growth, protein expression of RAR-alpha, beta and gamma, and RARE transcriptional activation were determined. Results and CONCLUSION: AT-RA reduces proliferation rates of immortal and weakly tumorigenic cells, but not highly tumorigenic cells. This loss of response of highly tumorigenic cells to AT-RA is associated with overexpression of p185(c-erbB2/neu). It is not associated with decreased RAR-alpha, beta or gamma expression, or activation by AT-RA; RAR-alpha, beta and gamma are expressed and AT-RA increases RARE transcriptional activity in all cell lines tested in this study.

PMID: 19661293 [PubMed - indexed for MEDLINE]


Nutr Rev. 2008 Jan;66(1):55-9.
Retinoic acid as cause of cell proliferation or cell growth inhibition depending on activation of one of two different nuclear receptors.

Wolf G.
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA. nutritionreview@ilsi.org
Abstract

Retinoic acid can combine with the nuclear retinoic acid receptor (RAR), leading to cell growth inhibition, as in certain tumors. Retinoic acid can also bind to the orphan nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta), resulting in stimulation of cell growth and inhibition of apoptosis. To bind to RAR, retinoic acid is carried into the nucleus by the cytosolic cellular retinoic acid-binding protein-II; to bind to PPAR beta/delta, it is transported into the nucleus by the cytosolic fatty acid-binding protein 5.

PMID: 18254885 [PubMed - indexed for MEDLINE]
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Old 06-10-2010, 08:42 PM   #2
Rich66
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Re: Vitamin-A Derivative Provides Clues To Better Breast Cancer Drugs

http://breast-cancer-research.com/content/12/4/R62
Anti-tumor effects of retinoids combined with trastuzumab or tamoxifen in breast cancer cells: induction of apoptosis by retinoid/trastuzumab combinations

Debbie C Koay , Cynthia Zerillo , Murli Narayan , Lyndsay N Harris and Michael P DiGiovanna
Breast Cancer Research 2010, 12:R62doi:10.1186/bcr2625

Published: 9 August 2010
Abstract (provisional)

Introduction

HER2 and estrogen receptor (ER) are important in breast cancer and are therapeutic targets of trastuzumab (Herceptin) and tamoxifen, respectively. Retinoids inhibit breast cancer growth, and modulate signaling by HER2 and ER. We hypothesized that treatment with retinoids and simultaneous targeting of HER2 and/or ER may have enhanced anti-tumor effects.
Methods

The effects of retinoids combined with trastuzumab or tamoxifen were examined in two human breast cancer cell lines in culture, BT474 and SKBR3. Assays of proliferation, apoptosis, differentiation, cell cycle distribution, and receptor signaling were performed.
Results

In HER2-overexpressing/ER+ BT474 cells, combining all-trans retinoic acid (atRA) with tamoxifen or trastuzumab synergistically inhibited cell growth, and altered cell differentiation and cell cycle. Only atRA/trastuzumab-containing combinations induced apoptosis. BT-474 and HER2-overexpressing/ER- SKBR3 cells were treated with a panel of retinoids (atRA, 9-cis-retinoic acid (9-cis-RA), 13-cis-retinoic acid (13-cis-RA), or N-(4-hydroxyphenyl) retinamide (fenretinide) (4-HPR)) combined with trastuzumab. In BT-474 cells, none of the single agents except 4-HPR induced apoptosis, but again combinations of each retinoid with trastuzumab did induce apoptosis. In contrast, in SKBR3 cells, the single retinoid agents did cause apoptosis; this was only modestly enhanced by addition of trastuzumab. The retinoid drug combinations altered signaling by HER2 and ER. Retinoids were inactive in trastuzumab-resistant BT474 cells.
Conclusions

Combining retinoids with trastuzumab maximally inhibits cell growth and induces apoptosis in trastuzumab-sensitive cells. Treatment with such combinations may have benefit for breast cancer patients.
The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.





Crit Rev Oncol Hematol. 2009 Dec 22. [Epub ahead of print]
Angioprevention with fenretinide: Targeting angiogenesis in prevention and therapeutic strategies.

Sogno I, Venè R, Ferrari N, De Censi A, Imperatori A, Noonan DM, Tosetti F, Albini A.
IRCCS MultiMedica, Milano, Italy.


Abstract

Clinical trials have revealed that N-(4-hydroxyphenyl) retinamide (4HPR; fenretinide), a synthetic retinoic acid derivative, is a highly active and promising therapeutic and chemopreventive agent. Fenretinide shows biological activity against numerous cancer types in vitro and in preclinical studies. Clinical trials have shown that fenretinide induces a significant reduction of second breast cancer in premenopausal women. Several studies on different neoplasms are ongoing, such as breast and ovarian cancer, neuroblastoma, glioblastoma, head and neck and skin cancers and others. It has minimal side effects in humans, so that trials in young women at high-risk of breast cancer and ovarian and for the prevention of other tumor types such as lung cancer could be envisaged. Here we review some ongoing clinical trials and evaluate the possible mechanisms underlying the secondary chemopreventive effects of 4HPR. In particular we report basic and translational data on the anti-angiogenic "angiopreventive" properties of fenretinide, its anti-invasive activity, its ability to induce apoptosis and to generate or enhance production of reactive oxygen species as possible molecular bases for a chemopreventive action in patients. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

PMID: 20034809 [PubMed - as supplied by publisher]
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