Broad spectrum and potent antitumor activities of YM155, a novel small‐molecule survivin suppressant, in a wide variety of human cancer cell lines and xenograft models

Nakahara, Takahito; Kita, Aya; Yamanaka, Kazuhiro; Mori, Masamichi; Amino, Nobuaki; Takeuchi, Masahiro; Tominaga, Fumiko; Kinoyama, Isao; Matsuhisa, Akira; Kudou, Masafumi; Sasamata, Masao

doi:10.1111/j.1349-7006.2010.01834.x

Cited by 134 publications

(168 citation statements)

References 36 publications

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“…65,66 Agents targeting survivin may provide encouragement for such treatments. The small-molecule YM155, which has shown promising growth inhibitory effects and potent antitumor activities in cell lines and xenograft models, 67,68 is the most well-studied survivin inhibitor. Although the drug's safety and tolerability have been confirmed, single-agent YM155, as monotherapy regimen, demonstrated only limited activity in patients with refractory diffuse large B-cell lymphoma in a phase II clinical study.…”

Section: Discussionmentioning

confidence: 99%

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

et al. 2015

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Survivin, a member of the inhibitor of apoptosis protein family, is overexpressed in a variety of human neoplasms. The prognostic significance of survivin expression in diffuse large B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is unclear. We used standard immunohistochemistry methods to quantify survivin expression in 463 patients with de novo diffuse large B-cell lymphoma who received the R-CHOP. Of the 463 patients, 269 (58%) had survivin overexpression with a cutoff of 425%, associated with an International Prognostic Index score of 42 (P = 0.015), disease in ≥ 2 extranodal sites (P = 0.011), and a high Ki-67 index (Po 0.0001). Among patients with activated B cell-like disease, the overall survival rate of survivin-positive patients was significantly lower than that of survivinnegative patients (P = 0.033); multivariate analysis confirmed that in these patients, survivin overexpression was an independent prognostic factor for survival. Among patients with wild-type p53 overexpression, the overall survival and progression-free survival rates of the survivin-positive group were significantly lower than those of the survivin-negative group (P = 0.035 and P = 0.04 respectively). In STAT3-positive patients, survivin overexpression was associated with significantly better survival. Among patients with activated B cell-like disease, survivin-positive compared with survivin-negative groups had significantly different gene expression signatures, including genes involved in mitosis or tumor cell proliferation. Our results indicate that survivin is an

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Section: Discussionmentioning

confidence: 99%

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

et al. 2015

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“…Moreover, we found that YM155 significantly enhanced the antitumor effect of erlotinib in EGFR mutation-positive NSCLC cells with PTEN loss both in vitro and in vivo. YM155, a small-molecule inhibitor of the expression of the antiapoptotic protein survivin, is currently in clinical development as the first survivin suppressant (18,19,(34)(35)(36). This drug was found to exhibit a favorable safety tolerability profile and moderate single-agent activity in a recent phase II trial with patients with advanced, refractory NSCLC (37).…”

Section: Discussionmentioning

confidence: 99%

Overcoming Erlotinib Resistance in EGFR Mutation–Positive Non–Small Cell Lung Cancer Cells by Targeting Survivin

Okamoto

Hatashita

et al. 2012

Molecular Cancer Therapeutics

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Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation-positive non-small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR-TKIs contributes to EGFR-TKI-induced apoptosis in EGFR mutationpositive NSCLC cells. We have now investigated the role of survivin expression in EGFR-TKI resistance induced by PTEN loss. The EGFR-TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation-positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation-positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT-survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation-positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR-TKI resistance in EGFR mutation-positive NSCLC.

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“…YM155 was identified in a high-throughput screen to identify agents that selectively block survivin promoter activity and is the most clinically advanced of this new class of agents (40). It has demonstrated activity against various tumor types in preclinical studies (19,(40)(41)(42)(43). We selected the VHL null 786-O and the VHL wild-type Caki-1 cell lines as models for our xenograft studies as they both displayed high basal survivin expression.…”

Section: Discussionmentioning

confidence: 99%

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

Carew

Espitia

Zhao

et al. 2015

Molecular Cancer Therapeutics

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Elevated expression of the antiapoptotic factor survivin has been implicated in cancer cell survival and disease progression. However, its specific contribution to renal cell carcinoma (RCC) pathogenesis is not well defined. We investigated the roles of survivin in RCC tumor progression, resistance to mTOR inhibitors, and evaluated the therapeutic activity of the survivin suppressant YM155 in RCC models. Here, we report that survivin expression levels were significantly higher in RCC cell lines compared with normal renal cells. Stable targeted knockdown of survivin completely abrogated the ability of 786-O RCC tumors to grow in mice, thus demonstrating its importance as a regulator of RCC tumorigenesis. We next explored multiple strategies to therapeutically inhibit survivin function in RCC. Treatment with the mTOR inhibitor temsirolimus partially diminished survivin levels and this effect was augmented by the addition of YM155. Further analyses revealed that, in accordance with their combined anti-survivin effects, YM155 significantly improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in xenograft models in vivo. Similar to pharmacologic inhibition of survivin, shRNA-mediated silencing of survivin expression not only inhibited RCC tumor growth, but also significantly sensitized RCC cells to temsirolimus therapy. Subsequent experiments demonstrated that the effectiveness of this dual survivin/mTOR inhibition strategy was mediated by a potent decrease in survivin levels and corresponding induction of apoptosis. Our findings establish survivin inhibition as a novel approach to improve RCC therapy that warrants further investigation.

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Broad spectrum and potent antitumor activities of YM155, a novel small‐molecule survivin suppressant, in a wide variety of human cancer cell lines and xenograft models

Cited by 134 publications

References 36 publications

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

Prognostic and biological significance of survivin expression in patients with diffuse large B-cell lymphoma treated with rituximab-CHOP therapy

Overcoming Erlotinib Resistance in EGFR Mutation–Positive Non–Small Cell Lung Cancer Cells by Targeting Survivin

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

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