Retinoid Receptors and the Induction of Apoptosis in Canine Osteosarcoma Cells.

Hong, Suk-In; Ohashi, Emi; Kadosawa, Tsuyoshi; Mochizuki, Manabu; Matsunaga, Satoru; Nishimura, Ryohei; Sasaki, Nobuo

doi:10.1292/jvms.62.469

Cited by 5 publications

(7 citation statements)

References 17 publications

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“…The results shown are from 1 representative experiment of 3 conducted. [7], but the difference in sensitivity to retinoids has not been clarified yet. This study is not sufficiently conducted to determine the role of each receptor on the effect of retinoids, but the results obtained here indicate that the receptor responsible for the antiproliferative effect of retinoids on canine MCT cells is not equal to those responsible for the effect on human mast cells.…”

Section: Discussionmentioning

confidence: 99%

“…In our laboratory, we have previously shown the effect of retinoids in canine osteosarcoma and melanoma cells [6,7,18]. Osteosarcoma cells showed significant growth inhibition when treated with retinoids, although significant growth inhibition was only seen when the cells were treated with the highest dose, 10 -5 M [6,7]. No effects on the growth rate or differentiation of melanoma cell lines were observed [18].…”

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confidence: 97%

“…There have only been few studies that have discussed the effect of retinoids on canine cancers [17,29]. In our laboratory, we have previously shown the effect of retinoids in canine osteosarcoma and melanoma cells [6,7,18]. Osteosarcoma cells showed significant growth inhibition when treated with retinoids, although significant growth inhibition was only seen when the cells were treated with the highest dose, 10 -5 M [6,7].…”

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confidence: 97%

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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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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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“…The RXR-RAR heterodimers have significant roles in most of the retinoidal activities by binding to a variety of retinoic acid receptor elements (RAREs) and regulate their trans-activation activities. The RAR affinities, or the activation abilities of retinoids, correlate well with their biological activities [6,20]. Specific ligands for RXRs alone cannot activate the RXR-RAR heterodimers, but they do regulate the activities of retinoids allosterically by binding the RXR site of the heterodimers [6].…”

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“…The RAR affinities, or the activation abilities of retinoids, correlate well with their biological activities [6,20]. Specific ligands for RXRs alone cannot activate the RXR-RAR heterodimers, but they do regulate the activities of retinoids allosterically by binding the RXR site of the heterodimers [6].All-trans retinoic acid (ATRA) and 9-cis retinoic acid (9CRA) are natural retinoids, and Am80 and HX630 are synthetic retinoids. ATRA activates only RARs, while 9CRA activates both RARs and RXRs [9].…”

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Effect of Natural and Synthetic Retinoids on the Proliferation and Differentiation of Three Canine Melanoma Cell Lines

Ohashi¹,

Inoué²,

Kagechika

et al. 2002

The Journal of Veterinary Medical Science

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ABSTRACT. The effect of two natural retinoids and synthetic retinoids with or without retinoid synergists on the proliferation and differentiation of 3 melanoma cell lines were investigated in vitro. No retinoids showed significant growth inhibitory effect on these cell lines when used alone, however, cell differentiation and significant growth inhibition were observed when treated with a combination of retinoids and a retinoid synergist. This study may suggest that, though the cells showed low susceptibilities when retinoids were treated alone, the combination of retinoids and a retinoid synergist may be effective to control the growth of canine melanoma cell lines. KEY WORDS: canine melanoma, retionoid.J. Vet. Med. Sci. 64(2): 169-172, 2002 Melanoma is a common neoplastic disease of dogs with variable biological behaviors. Melanomas account for 9-20% of skin tumors in dogs, and they are one of the most common malignant tumors of the oral cavity and of the digits in dogs [14]. Melanomas of the oral cavity are aggressive tumors that commonly metastasize to the regional lymph nodes and lung, and are poorly responsive to conventional therapy by the time they are discovered [14].The retinoids are a class of pharmacological agents consisting of vitamin A (retinol) and its derivatives. They have long been known to play a pivotal role in the development and maintenance of the normal epithelial tissue as well as growth, reproduction, immune function, and vision [23]. They have also been well recognized as promising anticancer agents. Preclinical studies, both in vitro and in vivo, suggest that retinoids may be effective in growth inhibition of many kinds of cancers [1,4,7,23], including melanoma [12,15,19,22]. The effects of retinoids are mainly mediated by two classes of nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Both RARs and RXRs are encoded by three distinct genes (α, β and γ) and are members of the steroid/thyroid hormone receptor superfamily that function as ligand-activated transcription factors [3,5,21]. The RXR-RAR heterodimers have significant roles in most of the retinoidal activities by binding to a variety of retinoic acid receptor elements (RAREs) and regulate their trans-activation activities. The RAR affinities, or the activation abilities of retinoids, correlate well with their biological activities [6,20]. Specific ligands for RXRs alone cannot activate the RXR-RAR heterodimers, but they do regulate the activities of retinoids allosterically by binding the RXR site of the heterodimers [6].All-trans retinoic acid (ATRA) and 9-cis retinoic acid (9CRA) are natural retinoids, and Am80 and HX630 are synthetic retinoids. ATRA activates only RARs, while 9CRA activates both RARs and RXRs [9]. Am80 can only bind to RARα and β, though their binding affinities are more potent than ATRA [9]. HX630 is a RXR-selective compound, which is so called retinoid synergists. Retinoid synergists are thought to be inactive alone because they cannot activate RXR-RAR heterodimers, but...

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Therapies for Neoplastic Disorders

Wynn¹

2003

Manual of Natural Veterinary Medicine

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Retinoid Receptors and the Induction of Apoptosis in Canine Osteosarcoma Cells.

Cited by 5 publications

References 17 publications

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

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

Effect of Natural and Synthetic Retinoids on the Proliferation and Differentiation of Three Canine Melanoma Cell Lines

Therapies for Neoplastic Disorders

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