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

Abstract

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...

Proliferation, angiogenesis and differentiation related markers in compact and follicular-compact thyroid carcinomas in dogs

“…The expression of RARα and RXR in healthy thyroid glands and thyroid carcinomas in dogs has not been reported previously. In humans, the expression of these retinoic receptors in healthy thyroid tissue, thyroid cell lines, and in thyroid adenomas and carcinomas has been reported (Hoftijzer et al, 2009); however, the expression of these receptors in dogs has only been described in lymphoma, melanoma and osteosarcoma Ohashi et al, 2006;de Mello Souza et al, 2010. In the present study, RARα expression in follicular cells did not differ in carcinomas and healthy thyroid glands.…”

Mastocitose

“…46 Estudos realizados com retinoides mostram seu efeito inibidor do crescimento celular e apoptótico dos mastócitos, sendo agentes antitumorais. 47 Quanto ao tratamento da mastocitose sistêmi-ca, não há um consenso, podendo-se utilizar várias formas terapêuticas. Os citorredutores (em especial a quimioterapia) são geralmente reservados para a mastocitose de evolução progressiva com organopatia documentada e infiltração mastocitária.…”

“…48 Comumente empregam-se agentes citostáticos e citorredutores de primeira e segunda linha, tais como: alfa-interferon, 2-clorodeoxiadenosina (cladribine; 2-Cda) e outros. 47,48 O tratamento da mastocitose sistêmica agressiva deve ser planejado com cautela, buscando o diagnósti-co da mastocitose sistêmica com ou sem comprometimento hematopoiético. 2 Na mastocitose sistêmica agressiva com alteração hematológica e na leucemia mastocítica, pode ser utilizado alfa-interferon com sucesso.…”

Post-surgical treatment of thyroid carcinoma in dogs with retinoic acid 9 cis improves patient outcome

“…In tumour cells culture lines and human TC, retinoic acid acts as anti-proliferative and redifferentiation agent of this disease (Coelho et al, 2005;Coelho et al, 2011;Oh et al, 2011;Trojanowicz et al, 2009). Although there has been investigated in vitro models for different tumours in dogs (de Mello Souza et al, 2010;Miyajima et al, 2006;Ohashi et al, 2006), there is only one report of using RA9-cis to treat Cushing's disease in dogs (Castillo et al, 2006). Our results clearly show that tumour recurrence is lower and survival time is longer in dogs treated with RA9-cis after surgery compared with dogs that were treated with doxorubicin.…”