Regulation of Retinoidal Actions by Diazepinylbenzoic Acids. Retinoid Synergists Which Activate the RXR−RAR Heterodimers

Umemiya, Hiroki; Fukasawa, Hiroshi; Ebisawa, Masayuki; Eyrolles, L.; Kawachi, Emiko; Eisenmann, Ghislaine; Gronemeyer, Hinrich; Hashimoto, Yuichi; Shudo, Koichi; Kagechika, Hiroyuki

doi:10.1021/jm9704309

Cited by 175 publications

(132 citation statements)

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“…Am80 is a synthetic retinoid that exhibits RAR alpha-selectivity with some RAR beta-binding ability. Although it has been reported that the RAR alpha-binding affinity of Am80 is higher than that of ATRA [27], its inhibitory effect on cell growth observed in this study was lower compared to ATRA. RAR alpha does not seem to be the major RAR subtype for the regulation of cell growth in MCT cells.…”

Section: Discussioncontrasting

confidence: 76%

“…ATRA activates only RARs, while 9cRA activates both RARs and RXRs [4,13,16,20]. Am80 can only bind to RAR alpha and beta, though their binding affinities are more potent than ATRA [27].The potential interaction between retinoids and cancer therapy has been recognized for decades, acute promyelocytic leukemia (APL) being the most notable example. APL can be effectively eradicated by retinoids, and therefore forms the prototype for retinoid-based therapies [22].…”

mentioning

confidence: 99%

“…ATRA activates only RARs, while 9cRA activates both RARs and RXRs [4,13,16,20]. Am80 can only bind to RAR alpha and beta, though their binding affinities are more potent than ATRA [27].…”

mentioning

confidence: 99%

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Retinoids Induce Growth Inhibition and Apoptosis in Mast Cell Tumor Cell Lines

Ohashi

Miyajima

Nakagawa

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. Retinoids are well recognized as promising antitumor agents in humans. However, there have only been a few reports about the effect of retinoids in canine cancers. To investigate the antitumor effect of retinoids on mast cell tumors (MCT), inhibitory effect on cell growth and induction of apoptosis were examined in vitro. Although sensitivity of these cells differed among the cells, the growth of three MCT cell lines (CoMS, CM-MC and VI-MC) were inhibited dose dependently when they were treated with retinoids. FACS analysis of PI-stained nuclei revealed an apoptotic fraction in CM-MC cells about 30% when treated with retinoids, while those of control cells were less than 5%. Caspase-3 activation was observed after retinoid treatment in CM-MC cells. This was confirmed by inhibiting the retinoid-induced apoptosis using the pan-caspase inhibitor, ZVAD-FMK. Both retinoid receptors, RARs and RXRs, were detected by immunoprecipitation followed by western blot analysis in all the three MCT cells. These data suggests that retinoids inhibit the growth of MCTs partly through apoptosis, and this growth inhibition by retinoids may be mediated by RARs and RXRs. We conclude that retinoid may be a potential adjunctive chemotherapeutic agent for the treatment of canine MCT. KEY WORDS: canine, mast cell tumor, retinoid.J. Vet. Med. Sci. 68(8): 797-802, 2006 Mast cell tumors (MCTs) represent the most common cutaneous tumor in the dog, accounting for between 16 to 21% of all cutaneous tumors [28]. Histologic grading, determined by the morphologic characteristics of the neoplastic cells, has been established as the most consistent prognostic factor highly predictive of biological behavior and clinical outcome [19]. The majority of dogs that suffer undifferentiated MCTs carry a poor prognosis [19]. Surgical excision and radiation therapy have been the most successful treatment modality for MCTs described to date, and the use of adjuvant chemotherapy is indicated after the excision of grade 3, metastatic and nonresectable MCTs [23]. However, chemotherapy for canine MCT has been unrewarding, and long-term responses have not been demonstrated in well-controlled clinical trials. Therefore, there is a need for chemotherapy to be improved in order to obtain a better prognosis in undifferentiated MCTs.Retinoids are active metabolites of vitamin A and modulate various biological functions such as cell differentiation, proliferation and embryonic development in vertebrates [11]. It has been well established that retinoidal activities result mainly from the transcriptional regulation of specific gene programs. Retinoids bind to and activate two classes of receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both of which belong to the steroid/thyroid hormone receptor superfamily [4,13,16,20]. Preclinical and clinical studies suggest that retinoids induce the growth inhibition of various kinds of cancers in human through differentiation and apoptosis. All-trans retinoic acid (ATRA) and 9-cis retinoic acid (9c...

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Section: Discussioncontrasting

confidence: 76%

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confidence: 99%

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Retinoids Induce Growth Inhibition and Apoptosis in Mast Cell Tumor Cell Lines

Ohashi

Miyajima

Nakagawa

et al. 2006

The Journal of Veterinary Medical Science

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“…To investigate if the enhancement of TRAIL-mediated apoptosis requires retinoid receptor activation, two pan-antagonists, one blocking the RAR receptors (LE540) and the other blocking the RXR receptors (HX531), were tested in the A547 and AD10 cell lines. 36,37 Preincubation with these antagonists did not inhibit the enhancement in TRAIL-mediated apoptosis induced by 4HPR in the cell lines tested (A547 shown in Figure 3b and AD10 not shown). To demonstrate that the inhibitors block RAR-or RXR-mediated effects, we treated the A547 cell line with ATRA plus TRAIL in the presence or absence of both inhibitors.…”

Section: The Combination Of 4hpr and Trail Induces Caspase-mediated Amentioning

confidence: 89%

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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“…In some experiments, cells were costimulated with t-RA (0.5 -5 M) and H 2 O 2 (150 M). To examine roles of RAR and RXR in the regulation of MKP-1 by retinoids, the following agonists and antagonists were used: RAR agonist TTNPB (0.1-1 M) (24), RXR agonist AGN194204 (1 nM to 1 M) (25), RAR/RXR panagonist 9-cis-RA (1 nM to 10 M), RAR␣ agonist Am580 (0.01 nM to 0.01 M) (26), RAR␤ agonist CD2314 (0.1 nM to 1 M) (27), RAR␥ agonist CD666 (0.1 nM to 1 M) (26), RAR antagonist AGN193109 (0.1-5 M) (24), RXR antagonist HX531 (0.1-5 M) (28,29), RAR␣ antagonist ER50891 (0.1 M) (30), RAR␤ antagonist LE135 (0.1 M) (31,32), and RAR␥ antagonist MM11253 (also known as SR11253; 0.1 M) (33,34). Cells were pretreated with or without 10 -50 times higher concentrations of antagonists for 10 min and then stimulated with agonists for 1 h.…”

Section: Methodsmentioning

confidence: 99%