Antitumor effects of YM155, a novel survivin suppressant, against human aggressive non-Hodgkin lymphoma

Kita, Aya; Nakahara, Takahito; Yamanaka, Kazuhiro; Nakano, Kenji; Nakata, Mari; Mori, Masamichi; Kaneko, Naoki; Koutoku, Hiroshi; Izumisawa, Nobuyuki; Sasamata, Masao

doi:10.1016/j.leukres.2010.11.016

Cited by 48 publications

(40 citation statements)

References 28 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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“…Erlotinib was administered by oral gavage daily for 31 days, with control animals receiving a 0.5% (w/v) aqueous solution of hydroxypropylmethylcellulose as vehicle. Continuous infusion of YM155 has been found to induce tumor regression and intratumoral survivin suppression in established human hormone-refractory prostate cancer, non-Hodgkin lymphoma, melanoma, and NSCLC xenografts (16)(17)(18)(19)(20). YM155 was thus administered over 7 consecutive days (days 1 to 7) with the use of an implanted micro-osmotic pump (Alzet model 1003D; DURECT Cupertino).…”

Section: Growth Inhibition Assay In Vivomentioning

confidence: 99%

“…YM155 is a small-molecule agent that specifically inhibits survivin expression in various types of cancer cell lines in vitro and in vivo (16)(17)(18)(19)(20). Treatment of PC9/GEF1-1 or PC9/GEF2-1 cells, or of parental PC9 cells, with YM155 resulted in downregulation of survivin expression (Fig.…”

Section: Ym155 Reverses Erlotinib Resistance Induced By Loss Of Pten mentioning

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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“…In pre-clinical experiments, YM155 as a single agent downregulated the transcription of survivin in a dose/time-dependent manner, triggering p53-independent apoptosis in a wide range of human tumor cells. YM155 also induced tumor regression in established cancer xenografts (24,25), and the combination of YM155 with various chemotherapeutic agents potentiated apoptosis induction in several human cancers (26)(27)(28). Despite its demonstrated efficacy in targeting tumor cells, the effects of YM155 in combination with DNA-damaging drugs have remained largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Survivin selective inhibitor YM155 promotes cisplatin-induced apoptosis in embryonal rhabdomyosarcoma

Ueno

Uehara

Nakahata

et al. 2016

International Journal of Oncology

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Abstract. Survivin, a member of the inhibitor of apoptosis protein family, functions as a key regulator of programmed cell death. YM155 is a small molecule that selectively inhibits survivin. We investigated the effect of YM155 on survivin suppression in the human rhabdomyosarcoma (RMS) cell line RD. The efficacy of YM155 in combination with cisplatin was also determined in a xenograft model. The effect of YM155 on survivin expression in the RD cell line was examined at both mRNA and protein levels using real-time PCR and western blot analysis. RD cells were cultured with various concentrations of YM155, then cisplatin was added to the medium and the anti-proliferation response was determined. Cell growth was evaluated by WST-8 assay. Finally, the efficacy of YM155 combined with cisplatin was examined in an established xenograft model. Survivin mRNA levels in the RD cell line were decreased to 72 and 24% at 24 and 48 h, respectively, after 10 nM of YM155 was added. YM155 also decreased the levels of survivin protein. YM155 treatment (10 nM) inhibited cell proliferation of RD in a dose-dependent manner in vitro, with 58% of cells viable at 48 h. When cultured with 10 nM of YM155 and 10 µM cisplatin, RD cells demonstrated only 25% of the growth observed when cultured with cisplatin alone. YM155 in combination with cisplatin significantly inhibited tumor growth by 13% compared with control (P<0.0001) in RD xenograft tumors. YM155 increased the sensitivity of cisplatin by suppressing survivin in the embryonal RMS cell line RD. Further studies should investigate the use of YM155 as an apoptosis inducer, either alone or in combination with cisplatin, for the treatment of malignant RMS.

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Antitumor effects of YM155, a novel survivin suppressant, against human aggressive non-Hodgkin lymphoma

Cited by 48 publications

References 28 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

Survivin selective inhibitor YM155 promotes cisplatin-induced apoptosis in embryonal rhabdomyosarcoma

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