Survivin suppressor (YM155) enhances chemotherapeutic efficacy against canine histiocytic sarcoma in murine transplantation models

Yamazaki, H.; Takagi, Satoshi; Hosoya, Kenji; Okumura, Masahiro

doi:10.1016/j.rvsc.2015.02.003

Cited by 8 publications

(4 citation statements)

References 25 publications

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“…In the present study, we have demonstrated that YM155 may enhance the anti-tumor efficacy of etoposide against canine OSA. While previous studies have shown that YM155 sensitizes cancer cells to conventional chemotherapeutic agents by inducing apoptosis [25, 29, 52, 53], our findings suggest that YM155 does not cause different canine OSA cell lines to undergo identical molecular changes that contribute to the enhanced anti-proliferative effects. Canine OSA is a heterogeneous group that can be classified into several histological subtypes [51].…”

Section: Discussioncontrasting

confidence: 75%

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YM155 enhances the cytotoxic activity of etoposide against canine osteosarcoma cells

Ong

Saeki

Kok

et al. 2019

The Journal of Veterinary Medical Science

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Canine osteosarcoma (OSA) is an aggressive and highly malignant primary bone tumor. Its poor survival outcome remains problematic despite recent advances in anti-cancer therapy, therefore highlighting the need for alternative treatment options or drug repositioning. The aim of this study was to determine if YM155, a small-molecule survivin inhibitor, potentiates the chemotherapeutic efficacy of etoposide against canine OSA in vitro and in vivo . In cell culture, YM155 enhanced the cytotoxic effect of etoposide against canine OSA cell lines; however, the molecular mechanism behind this effect was heterogeneous, as only one cell line had an elevated apoptotic level. In addition, this effect was not associated with survivin suppression in two of the cell lines. These results suggest that the molecular target of YM155 is not restricted to survivin alone. When tested on a murine xenograft model, the average tumor volume of the combination treatment group (YM155, 5 mg/kg, intraperitoneally, 5 consecutive days/week; and etoposide, 20 mg/kg, intraperitoneally, every 5 days) was 66% smaller than the control group, although this difference was not statistically significant ( P =0.17). Further studies to improve the treatment protocol are necessary to confirm the findings of this study.

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Section: Discussioncontrasting

confidence: 75%

“…YM155 is a small-molecule that selectively suppresses survivin promoter activity and its subsequent protein expression, resulting in apoptosis in a broad array of human cancer cell lines and mouse xenograft models [3, 12, 25, 28, 34, 52]. Furthermore, it chemosensitizes both human and canine cancer cells to cytotoxic agents [19, 25, 29, 53, 55].…”

mentioning

confidence: 99%

YM155 enhances the cytotoxic activity of etoposide against canine osteosarcoma cells

Ong

Saeki

Kok

et al. 2019

The Journal of Veterinary Medical Science

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“…Further studies with a larger number of animals are warranted to truly establish the transplantability and metastatic potential. A few xenograft mouse models of canine HS have been successfully established and were used for the evaluation of their metastatic potential, and to study the phenomenon of resistance to CCNU-based treatment [ 45 , 46 ]; however, none of these cell lines had originated from BMDs, the most frequently affected breed. To the best of our knowledge, across the many existent canine HS cell lines, only two others were reported to be originated from tumors of BMDs [ 47 ]; and these two were not part of their drug response report.…”

Section: Discussionmentioning

confidence: 99%

A novel canine histiocytic sarcoma cell line: initial characterization and utilization for drug screening studies

et al. 2018

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BackgroundHistiocytic sarcoma is a rare disorder in humans, however it is seen with appreciable frequency in certain breeds of dogs, such as Bernese mountain dog. The purpose of this study was to fully characterize a novel canine histiocytic sarcoma cell line, and utilize it as a tool to screen for potential therapeutic drugs.MethodsThe histiocytic sarcoma cell line was characterized by expression of cellular markers as determined by immunohistochemistry and flow cytometry techniques. The neoplastic cells were also evaluated for their capability of phagocytizing beads particles, and their potential to grow as xenograft in an immunodeficient mouse. We investigated the in vitro cytotoxic activity of a panel of thirteen compounds using the MTS proliferation assay. Inhibitory effects of different drugs were compared using one-way ANOVA, and multiple means were compared using Tukey’s test.ResultsNeoplastic cells expressed CD11c, CD14, CD18, CD45, CD172a, CD204, MHC I, and vimentin. Expression of MHC II was upregulated after exposure to LPS. Furthermore, the established cell line clearly demonstrated phagocytic activity similar to positive controls of macrophage cell line. The xenograft mouse developed a palpable subcutaneous soft tissue mass after 29 days of inoculation, which histologically resembled the primary neoplasm. Dasatinib, a tyrosine kinase pan-inhibitor, significantly inhibited the growth of the cells in vitro within a clinically achievable and tolerable plasma concentration. The inhibitory response to dasatinib was augmented when combined with doxorubicin.ConclusionsIn the present study we demonstrated that a novel canine histiocytic sarcoma cell line presents a valuable tool to evaluate novel treatment approaches. The neoplastic cell line favorably responded to dasatinib, which represents a promising anticancer strategy for the treatment of this malignancy in dogs and similar disorders in humans.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4132-0) contains supplementary material, which is available to authorized users.

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“…Although no human HS xenograft model has been reported in the literature to date, xenograft models of subcutaneous canine HS were successfully established in 2 studies, but neither of these models developed metastatic disease. 3,39 Other authors described a xenograft model that presented as disseminated…”

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Development of an Orthotopic Intrasplenic Xenograft Mouse Model of Canine Histiocytic Sarcoma and Its Use in Evaluating the Efficacy of Treatment with Dasatinib

et al. 2019

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Canine histiocytic sarcoma (HS), historically called malignant histiocytosis, is a highly aggressive hematopoietic neoplasm of malignant cells of dendritic cell lineage. Although rare (fewer than 1% of all cancers), 5 several dog breeds are highly predisposed to HS, including Bernese mountain dogs (more than 25% of the population), 1,10 flat-coated retrievers, 11,12 golden retrievers, and Rottweilers. 2,7,30 Canine HS most frequently develops in the spleen, lymph nodes, liver, lung, and bone marrow, 2,23 where it progresses rapidly, disseminating to multiple organs in 70% to 91% of cases. 7,12,23,30 Due to the lack of effective options for treatment, patients respond poorly to available protocols, resulting in survival times that range from a few weeks to 3 mo. 14,28,30 Studies by our group using HS cell lines in culture have indicated dasatinib as a potential treatment option for dogs with HS. 34 Other research groups shared similar results after testing dasatinib in HS cell lines 17 and in a subcutaneous xenograft mouse model of HS. 18 Dasatinib is a tyrosine kinase inhibitor of multiple targets including SRC family kinases (SRC, LCK, YES, and FYN). This drug is approved for people with Philadelphia chromosome-positive chronic myeloid leukemia or acute lymphoblastic leukemia. 31 The efficacy of dasatinib in dogs and humans with HS is unknown.Human HS is a similar and equally aggressive malignancy to canine HS and is extremely rare, accounting for less than 1% of all hematopoietic neoplasms. 19,20 In humans, HS is associated with a poor prognosis and a survival time of less than 1 y. 24,38 Human HS may present as a localized disease that is treatable with surgical resection or radiation therapy; however, it typically presents at an advanced stage that involves multiple organs, including lymph nodes, the gastrointestinal tract, spleen, and lungs. 16,29,35 Patients with disseminated disease have a poor prognosis due to limited response to available treatments. 13,16 Studies to identify more effective therapeutic approaches are warranted, but given the low incidence of HS in humans, research progress is slow. Dogs are the only species that spontaneously develops a similar form of HS at an appreciable frequency, thus representing an important translational model for this rare disease in humans.Xenograft mouse models are important tools to evaluate the in vivo response to novel cancer therapeutic interventions. Although no human HS xenograft model has been reported in the literature to date, xenograft models of subcutaneous canine HS were successfully established in 2 studies, but neither of these models developed metastatic disease. 3,39 Other authors described a xenograft model that presented as disseminated

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Survivin suppressor (YM155) enhances chemotherapeutic efficacy against canine histiocytic sarcoma in murine transplantation models

Cited by 8 publications

References 25 publications

YM155 enhances the cytotoxic activity of etoposide against canine osteosarcoma cells

YM155 enhances the cytotoxic activity of etoposide against canine osteosarcoma cells

A novel canine histiocytic sarcoma cell line: initial characterization and utilization for drug screening studies

Development of an Orthotopic Intrasplenic Xenograft Mouse Model of Canine Histiocytic Sarcoma and Its Use in Evaluating the Efficacy of Treatment with Dasatinib

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