Cytodifferentiation by Retinoids, a Novel Therapeutic Option in Oncology: Rational Combinations with Other Therapeutic Agents

Garattini, Enrico; Giannı̀, Maurizio; Terao, Mineko

doi:10.1016/s0083-6729(06)75012-9

Cited by 25 publications

(20 citation statements)

References 248 publications

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“…This interesting biological activity profile of retinoids has prompted investigators to study them in the chemoprevention of epithelial cancers and in the treatment of advanced cancers (Lippman et al, 1994;Sankaranarayanan and Mathew, 1996). Although the therapeutic response of retinoids against advanced cancers is disappointing, retinoids interact in vitro with conventional cytotoxic drugs such as cisplatin and the taxanes paclitaxel and docetaxel to lower the threshold of apoptosis (Jozan and Lafon, 1996;Aebi et al, 1997;Wang et al, 2000;Nehme et al, 2001;Jozan et al, 2002;Wang and Wieder, 2004;Garattini et al, 2007). This study had investigated that ATRA could significantly prolong OS of the patients with gastric cancer combined conventional chemotherapy with a substantially better benefit to toxicity ratio and the expression of RARa was correlated with the responsiveness to ATRA.…”

Section: Discussionmentioning

confidence: 99%

Retinoid Receptors in Gastric Cancer: Expression and Influence on Prognosis

Chen²,

Ge³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Retinoic acid has been recognised as a pivotal compound in cell differentiation, proliferation and malignant transformation (Shyu et al., 1995;Tanaka and De Luca, 2009). Retinoids are natural and synthetic derivatives of retinol (vitamin A). The naturally occuring retinoids, all-trans retinoic acid, 9-cis retinoic acid and 13-cis retinoic acid, are generated from diet-derived retinol. Retinoids are ligands of cellular receptors of retinoic acid, including retinoic acid receptors (RARs) and retinoid X receptors (RXRs) who are members of the steroid and thyroid hormone receptor superfamily (Evans, 1998;Sun and Lotan, 2002). Each subtype of both retinoid receptor classes (RARa, RARβ, RARγ and RXRa, RXRβ, RXRγ respectively) is encoded by separate genes. Multiple isoforms of receptor subtypes exist as a result of

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Section: Discussionmentioning

confidence: 99%

Retinoid Receptors in Gastric Cancer: Expression and Influence on Prognosis

Chen²,

Ge³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Alterations in pathways controlling cell proliferation and death/survival, transcription/translation, chromatin structure, and cytoskeletal organization may simply reflect a tissue-remodeling effect due to perturbations of local and AOH2-dependent ATRA synthesis. In this context, the enrichment of the Wnt/␤-catenin pathway is of relevance, as ATRA is known to exert numerous modulating effects on this signal transduction system (26,27).…”

Section: Discussionmentioning

confidence: 99%

Role of the Molybdoflavoenzyme Aldehyde Oxidase Homolog 2 in the Biosynthesis of Retinoic Acid: Generation and Characterization of a Knockout Mouse

Terao

Kurosaki

Barzago

et al. 2009

Molecular and Cellular Biology

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The mouse aldehyde oxidase AOH2 (aldehyde oxidase homolog 2) is a molybdoflavoenzyme. Harderian glands are the richest source of AOH2, although the protein is detectable also in sebaceous glands, epidermis, and other keratinized epithelia. The levels of AOH2 in the Harderian gland and skin are controlled by genetic background, being maximal in CD1 and C57BL/6 and minimal in DBA/2, CBA, and 129/Sv strains. Testosterone is a negative regulator of AOH2 in Harderian glands. Purified AOH2 oxidizes retinaldehyde into retinoic acid, while it is devoid of pyridoxal-oxidizing activity. Aoh2 ؊/؊ mice, the first aldehyde oxidase knockout animals ever generated, are viable and fertile. The data obtained for this knockout model indicate a significant role of AOH2 in the local synthesis and biodisposition of endogenous retinoids in the Harderian gland and skin. The Harderian gland's transcriptome of knockout mice demonstrates overall downregulation of direct retinoid-dependent genes as well as perturbations in pathways controlling lipid homeostasis and cellular secretion, particularly in sexually immature animals. The skin of knockout mice is characterized by thickening of the epidermis in basal conditions and after UV light exposure. This has correlates in the corresponding transcriptome, which shows enrichment and overall upregulation of genes involved in hypertrophic responses.Aldehyde oxidases (AOXs) (EC 1.2.3.1) are structurally conserved proteins belonging to the family of molybdoflavoenzymes along with xanthine oxidoreductase (XOR), the key enzyme in the catabolism of purines (25,28). In their catalytically active form, both AOXs and XORs are dimers of identical subunits characterized by three conserved domains separated by nonconserved hinge regions (28). The amino-terminal 25-kDa domain contains two nonidentical 2Fe-2S redox centers. The flavin adenine dinucleotide binding region is located in the intermediate 45-kDa domain, while the substrate and the molybdopterin cofactor binding pocket reside in the carboxy-terminal 85-kDa domain (28). AOXs have broad substrate specificity, hydroxylating N-heterocycles or oxidizing aliphatic as well as aromatic aldehydes into the corresponding acids (35,41,42).The primary structures of mammalian AOXs and XORs are more than 40% identical, and the two types of enzymes are evolutionary related. Most of the available data indicate that AOXs evolved from a primordial form of XOR through a series of gene duplication events (28). In mammals, the number of AOX genes is variable and species specific (25,28,37,65). Rodents have four AOX genes (Aox1, Aoh1, Aoh2, and Aoh3) which are the products of asynchronous duplication events and cluster at a short distance from one another on the same chromosome (chromosome 1c1 in mice and chromosome 9 in rats) (Fig. 1). The Aoh1, Aoh2, and Aoh3 genes are also known as Aox3, Aox4, and Aox3l, respectively, and are currently designated with the latter names in the NCBI database.(The designation of the four mouse AOX genes as Aox1, Aox3, Aox4, and Aox3l in...

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“…Suppression of RARγ activity enhances the antiproliferative effects of ATRA in cultures of breast cancer cell lines and in an appropriate animal model of the tumor. Finally, the RARα agonist AM580 [2] is more effective than the pan-RAR ligand, ATRA [3,4], in controlling the growth of breast cancer cells both in vitro and in vivo . This is consistent with the intrinsic ability of ATRA to activate RARα and RARγ simultaneously.…”

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confidence: 99%

“…ATRA is the only example of a clinically useful cyto-differentiating agent in oncology [3,4], having changed the natural history of acute promyelocytic leukemia, a rare form of acute myelogenous leukemia [5]. This along with promising results obtained in preclinical models has spurred interest in the use of ATRA and natural (9- cis and 13- cis retinoic acid) or synthetic derivatives (retinoids) also for the management of solid tumors, with particular reference to breast cancer.…”

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confidence: 99%

“…The use of RARα agonists should theoretically avoid activation of RARβ, whose expression in tumor-associated stromal cells is a potential determinant of breast cancer growth [15]. In addition, selective targeting of RARα may reduce certain aspects of retinoid systemic and dose-limiting toxicity, such as skin rashes and intra-cranial hypertension [3,4], two effects that are believed to be mediated by RARγ. However, simple activation of RARα may not be an optimal strategy to counter breast cancer growth and progression, as such an approach does not take into consideration the circulating levels of endogenous ATRA (1 to 10 nM) that are sufficient to activate tumor cells' RARγ.…”

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confidence: 99%

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Retinoids and breast cancer: new clues to increase their activity and selectivity

2012

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All-trans retinoic acid and derivatives (retinoids) are promising agents in the management of certain hematologic malignancies and solid tumors, including breast cancer. Retinoids are endowed with anti-proliferative, cyto-differentiating and apoptotic effects that are largely mediated by activation of the nuclear hormone retinoic acid receptors RARα, RARβ and RARγ. These are ligand-dependent transcriptional factors controlling the expression of numerous genes. The relative importance of each receptor subtype for the anti-tumor activity of retinoids is largely unknown. Clarification of this point is of fundamental importance for the rational design of retinoid-based therapeutic approaches aimed at controlling a heterogeneous type of tumors, like breast cancer.

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Cytodifferentiation by Retinoids, a Novel Therapeutic Option in Oncology: Rational Combinations with Other Therapeutic Agents

Cited by 25 publications

References 248 publications

Retinoid Receptors in Gastric Cancer: Expression and Influence on Prognosis

Retinoid Receptors in Gastric Cancer: Expression and Influence on Prognosis

Role of the Molybdoflavoenzyme Aldehyde Oxidase Homolog 2 in the Biosynthesis of Retinoic Acid: Generation and Characterization of a Knockout Mouse

Retinoids and breast cancer: new clues to increase their activity and selectivity

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