Marked anti-tumour activity of the combination of YM155, a novel survivin suppressant, and platinum-based drugs

Iwasa, Tsutomu; Okamoto, Isamu; Takezawa, Ken; Yamanaka, Kazuhiro; Nakahara, Takahito; Kita, Aya; Koutoku, Hiroshi; Sasamata, Masao; Hatashita, Erina; Yamada, Yoshiaki; Kuwata, Kiyoko; Fukuoka, Masahiro; Nakagawa, Kazuhiko

doi:10.1038/sj.bjc.6605713

Cited by 58 publications

(43 citation statements)

References 42 publications

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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%

“…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%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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

confidence: 99%

Section: Growth Inhibition Assay In Vivomentioning

confidence: 99%

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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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“…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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“…The continuous infusion of YM155 induced tumor regression in mice xenograft models (Nakahara et al, 2011a). Other results suggested that YM155 sensitized tumor cells to radiation (Iwasa et al, 2008) and platinum compounds both in vitro and in vivo, and that the effect was likely attributable to the inhibition of DNA repair and consequent enhancement of apoptosis (Iwasa et al, 2010). Non-clinical studies using radioactive 14 Clabeled YM155 demonstrated that the organic cation transporter 1 (OCT1) was the predominant transporter for the hepatic uptake of YM155 (Iwai et al, 2009).…”

Section: Determination Of Early Tumor Response To Anticancer Drugsmentioning

confidence: 99%

Radioisotopes in Drug Research and Development: Focus on Positron Emission Tomography

Miyoshi¹,

Mitsuoka²,

Nishimura³

et al. 2011

Radioisotopes - Applications in Bio-Medical Science

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Marked anti-tumour activity of the combination of YM155, a novel survivin suppressant, and platinum-based drugs

Cited by 58 publications

References 42 publications

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

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

Radioisotopes in Drug Research and Development: Focus on Positron Emission Tomography

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