Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

Carew, Jennifer S.; Espitia, Claudia M.; Zhao, Weiguo; Mita, Monica; Mita, Alain C.; Nawrocki, Steffan T.

doi:10.1158/1535-7163.mct-14-1036

Cited by 20 publications

(19 citation statements)

References 48 publications

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“…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]. However, YM155 treatment did not affect growth and apoptosis of poor-survivin expressed SCC25 cells, suggesting YM155 could be a target for the treatment of survivin-rich expressed OSSC.…”

Section: Discussionsupporting

confidence: 86%

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: 86%

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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“…3D ). Forced expression of survivin conveying chemo-radioresistance has also been described previously, and overexpression of survivin in HeLa cells resulted in resistance to paclitaxel ( 16 ), and resistance to temsirolimus in the renal cancer 786-O cell line ( 35 ). Overexpression of Multidrug resistance gene and survivin in RPMI8226/VCR multiple myeloma cells conferred multidrug resistance ( 36 ).…”

Section: Discussionsupporting

confidence: 55%

Growth inhibition and chemo‑radiosensitization of esophageal squamous cell carcinoma by survivin‑shRNA lentivirus transfection

Zhou

Zhang

2018

Oncol Lett

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Esophageal cancer is one of the most common types of cancer worldwide, and it has a poor prognosis. Chemo-radiotherapy resistance and cancer relapse are among the most difficult issues in its treatment. Identifying the underlying molecular mechanisms is critical for developing novel therapies. Survivin has been previously suggested to be overexpressed in esophageal cancer cells. The present study identified that down-regulation of survivin sensitized esophageal cancer cells to chemo-radiotherapy. Consistent with previous studies, the present study indicated that survivin was overexpressed in 4 esophageal squamous carcinoma cell lines. Short hairpin RNA delivered by lentivirus successfully knocked down survivin in these cancer cell lines. Consequently, down-regulation of survivin impaired their colony-forming, migratory and invasive capabilities, while the overexpression of survivin in normal human esophagus epithelial cells improved their resistance to cisplatin, paclitaxel and radiation. Survivin knockdown induced apoptosis in esophageal cancer KYSE-150 and ECA-109 cell lines when exposed to the aforementioned chemo-radiotherapy treatments. These results indicate that survivin expression sustains growth in esophageal cancer cells, and confers resistance to chemo-radiotherapy. Targeted survivin ablation may be a promising strategy against esophageal tumor relapse and chemo-radioresistance.

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“…Earlier, YM155 was reported to augment the activity of temsirolimus, a widely employed targeted therapy for RCC, in xenograft models [56]. The tyrosine kinase inhibitor sorafenib is widely endorsed as a standard of care for RCC and an alternative to temsirolimus.…”

Section: Resultsmentioning

confidence: 99%

Action of YM155 on clear cell renal cell carcinoma does not depend on survivin expression levels

Sim

Huynh

et al. 2017

PLoS ONE

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The dioxonapthoimidazolium YM155 is a survivin suppressant which has been investigated as an anticancer agent in clinical trials. Here, we investigated its growth inhibitory properties on a panel of immortalized and patient derived renal cell carcinoma (RCC) cell lines which were either deficient in the tumour suppressor von Hippel-Lindau (VHL) protein or possessed a functional copy. Neither the VHL status nor the survivin expression levels of these cell lines influenced their susceptibility to growth inhibition by YM155. Of the various RCC lines, the papillary subtype was more resistant to YM155, suggesting that the therapeutic efficacy of YM155 may be restricted to clear cell subtypes. YM155 was equally potent in cells (RCC786.0) in which survivin expression had been stably silenced or overexpressed, implicating a limited reliance on survivin in the mode of action of YM155. A follow-up in-vitro high throughput RNA microarray identified possible targets of YM155 apart from survivin. Selected genes (ID1, FOXO1, CYLD) that were differentially expressed in YM155-sensitive RCC cells and relevant to RCC pathology were validated with real-time PCR and western immunoblotting analyses. Thus, there is corroboratory evidence that the growth inhibitory activity of YM155 in RCC cell lines is not exclusively mediated by its suppression of survivin. In view of the growing importance of combination therapy in oncology, we showed that a combination of YM155 and sorafenib at ½ x IC50 concentrations was synergistic on RCC786.0 cells. However, when tested intraperitoneally on a murine xenograft model derived from a nephrectomised patient with clear cell RCC, a combination of suboptimal doses of both drugs failed to arrest tumour progression. The absence of synergy in vivo highlighted the need to further optimize the dosing schedules of YM155 and sorafenib, as well as their routes of administration. It also implied that the expression of other oncogenic proteins which YM155 may target is either low or absent in this clear cell RCC.

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Targeting Survivin Inhibits Renal Cell Carcinoma Progression and Enhances the Activity of Temsirolimus

Cited by 20 publications

References 48 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

Growth inhibition and chemo‑radiosensitization of esophageal squamous cell carcinoma by survivin‑shRNA lentivirus transfection

Action of YM155 on clear cell renal cell carcinoma does not depend on survivin expression levels

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