Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues

Cheng, Xiao; Lin, Jieyu; Ding, Yan; Zhu, Liming; Ye, Jing; Tu, Shikui

doi:10.18632/oncotarget.6898

Cited by 30 publications

(31 citation statements)

References 49 publications

(53 reference statements)

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“…This small imidazolium compound was initially identified from a pharmacological screen based on BIRC5 promoter inhibition and described as a first in class "Survivin suppressant". YM155 has been demonstrated to exert antitumor activity, to suppress Survivin expression and to induce tumor cell apoptosis and inhibit cell metastasis, in various human cancer models [13,14,[16][17][18]. Our current data show that YM155 not only inhibits cell growth but also induces apoptotic cell death of survivin-rich expressed SCC9 cells, a finding similar to those observed in Melanoma [25], renal Cell Carcinoma [26], multiple myeloma [27] and head neck squamous cell carcinoma [28,29].…”

Section: Discussionsupporting

confidence: 85%

“…Its primary functions comprise inhibiting apoptosis and regulating mitosis, which are associated with metastasis and carcinogenesis [8][9][10][11]. YM155, a novel small-molecule surviving suppressant, selectively suppresses surviving expression, resulting in the induction of apoptosis and invasion inhibition in various malignancies [12][13][14][15][16]. Furthermore, treatment with YM155 did not affecting normal tissues [13].…”

Section: Introductionmentioning

confidence: 99%

“…YM155, a novel small-molecule surviving suppressant, selectively suppresses surviving expression, resulting in the induction of apoptosis and invasion inhibition in various malignancies [12][13][14][15][16]. Furthermore, treatment with YM155 did not affecting normal tissues [13]. In clinical settings, YM155 was shown to be tolerable in phase I studies with advanced cancer patients and showed antitumor activity in NHL and HRPC subjects [17,18].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting of Survivin Pathways by YM155 Inhibits Cell Death and Invasion in Oral Squamous Cell Carcinoma Cells

Zhang

Liu

et al. 2016

Cell Physiol Biochem

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Background/Aims: Specific overexpression in cancer cells and evidence of oncogenic functions make Survivin an attractive target in cancer therapy. The small molecule compound YM155 has been described as the first “Survivin suppressant” but molecular mechanisms involved in its biological activity and its clinical potential remain obscure. Survivin protein plays critical roles in oral squamous cell carcinoma (OSCC), suggesting that YM155 would be extremely valuable for OSCC. In this study, we tested our hypothesis whether YM155 could be an effective inhibitor of cell growth, invasion and angiogenesis in oral squamous cell carcinoma (OSCC) cells. Methods: SCC9 and SCC25 were treated with different concentration of YM155 for indicated time. Using MTT assay and flow cytometry analysis to detect cell growth and apoptosis; Using transwell and Wound healing assay to detect migration and invasion; Using reverse transcription-PCR, Western blotting and electrophoretic mobility shift assay for measuring gene and protein expression, and DNA binding activity of NF-κB. Results: YM155 inhibited survivin-rich expressed SCC9 cell growth in a dose- and time dependent manner. This was accompanied by increased apoptosis and concomitant attenuation of NF-κB and downregulation of NF-κB downstream genes MMP-9, resulting in the inhibition of SCC9 cell migration and invasion in vitro and caused antitumor activity and anti metastasis in vivo. YM155 treatment did not affect cell growth, apoptosis and invasion of surviving-poor expressed SCC25 cells in vitro. Conclusions: YM155 is a potent inhibitor of progression of SCC9 cells, which could be due to attenuation of survivin signaling processes. Our findings provide evidence showing that YM155 could act as a small molecule survivin inhibitor on survivin-rich expressed SCC9 cells in culture as well as when grown as tumor in a xenograft model. We also suggest that survivin could be further developed as a potential therapeutic agent for the treatment of survivin-rich expressed OSCC.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting of Survivin Pathways by YM155 Inhibits Cell Death and Invasion in Oral Squamous Cell Carcinoma Cells

Zhang

Liu

et al. 2016

Cell Physiol Biochem

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“…Evaluation of the effect of YM155 in in vivo models for gastric carcinoma and osteosarcoma demonstrated a suppression of tumor growth in mice [48], [49]. The mechanism of action of YM155 as anticancer drug is still a matter of debate.…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

Graaff

Malu

Guardiola

et al. 2017

Translational Oncology

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Myxoid liposarcoma (MLS) is a soft tissue sarcoma characterized by a recurrent t(12;16) translocation. Although tumors are initially radio- and chemosensitive, the management of inoperable or metastatic MLS can be challenging. Therefore, our aim was to identify novel targets for systemic therapy. We performed an in vitro high-throughput drug screen using three MLS cell lines (402091, 1765092, DL-221), which were treated with 273 different drugs at four different concentrations. Cell lines and tissue microarrays were used for validation. As expected, all cell lines revealed a strong growth inhibition to conventional chemotherapeutic agents, such as anthracyclines and taxanes. A good response was observed to compounds interfering with Src and the mTOR pathway, which are known to be affected in these tumors. Moreover, BIRC5 was important for MLS survival because a strong inhibitory effect was seen at low concentration using the survivin inhibitor YM155, and siRNA for BIRC5 decreased cell viability. Immunohistochemistry revealed abundant expression of survivin restricted to the nucleus in all 32 tested primary tumor specimens. Inhibition of survivin in 402-91 and 1765-92 by YM155 increased the percentage S-phase but did not induce apoptosis, which warrants further investigation before application in the treatment of metastatic MLS. Thus, using a 273-compound drug screen, we confirmed previously identified targets (mTOR, Src) in MLS and demonstrate survivin as essential for MLS survival.

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“…Currently, the most intensively investigated survivin antagonist is the small imidazolium-based compound YM155 (Sepantronium bromide). This small molecule survivin inhibitor demonstrated impressive anticancer activity in several preclinical studies using cancer cell lines originating from various types of cancer, including GC cells (30,(48)(49)(50) and was well tolerated in phase I studies (51,52). Concerning the potential efficacy of anti-XIAP treatment strategies in GC initial promising results have been published.…”

Section: Svv (Cyt)-center Svv (Cyt)-invasion ----------------------mentioning

confidence: 99%

Survivin and XIAP expression in distinct tumor compartments of surgically resected gastric cancer: XIAP as a prognostic marker in diffuse and mixed type adenocarcinomas

et al. 2017

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Abstract. There is considerable evidence that the inhibitor of apoptosis protein (IAP) family serves a role in tumorigenesis. The most studied IAP family members, survivin and X-linked inhibitor of apoptosis (XIAP), have been demonstrated to serve as biomarkers in distinct tumor entities. Thus, the present study aimed to investigate the expression levels of both IAPs in the tumor center, invasion front and lymph node metastases of surgically resected gastric cancer (GC) specimens. Tissue microarrays containing samples from 201 primary GCs were analyzed. IAP expression was detected using immunohistochemistry in different tumor compartments, normal mucosa and lymph node metastases. In addition, the association between the expression levels of these proteins, and clinicopathological parameters and overall survival was investigated. High levels of survivin and XIAP were evident in GC, when compared with normal mucosa, and were correlated with intestinal-type and well-differentiated GC, as well as low International Union Against Cancer stages. Increased XIAP expression was detected in lymph node metastases as compared with corresponding primary tumors. XIAP overexpression was identified to be an independent negative prognostic marker in diffuse and mixed type GC. These results suggest a potential role of survivin and XIAP in the early phase of gastric carcinogenesis. In addition, increased XIAP expression in lymph node metastases supports the observation that IAPs serve an essential role in metastatic tumor disease. Since XIAP expression was identified to be associated with poor survival in diffuse and mixed type GC, XIAP may serve as a novel therapeutic target in these types of GC.

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Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues

Cited by 30 publications

References 49 publications

Targeting of Survivin Pathways by YM155 Inhibits Cell Death and Invasion in Oral Squamous Cell Carcinoma Cells

Targeting of Survivin Pathways by YM155 Inhibits Cell Death and Invasion in Oral Squamous Cell Carcinoma Cells

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

Survivin and XIAP expression in distinct tumor compartments of surgically resected gastric cancer: XIAP as a prognostic marker in diffuse and mixed type adenocarcinomas

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