YM155, a novel survivin suppressant, enhances taxane-induced apoptosis and tumor regression in a human Calu 6 lung cancer xenograft model

Nakahara, Takahito; Yamanaka, Kazuhiro; Hatakeyama, Shinji; Kita, Aya; Takeuchi, Masahiro; Kinoyama, Isao; Matsuhisa, Akira; Nakano, Kenji; Shishido, Toetsu; Koutoku, Hiroshi; Sasamata, Masao

doi:10.1097/cad.0b013e328344ac68

Cited by 56 publications

(42 citation statements)

References 31 publications

(45 reference statements)

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“…Thus, we also tested the cytotoxic effects of YM155 combined with cisplatin, gemcitabine, or both. YM155 has been reported to potentiate the therapeutic effects of many chemotherapy or targeted-therapy agents (13,14,(35)(36)(37)(38)(39). However, our results demonstrated that YM155 alone exerted potent cytotoxicity in BFTC905 cells, and addition of cisplatin and/or gemcitabine to YM155 did not elicit synergistic or additive effects.…”

Section: Discussioncontrasting

confidence: 53%

“…Sepantronium bromide, a small molecule also known as YM155, directly binds to the transcription factor ILF3/NF110 or disrupts ILF3/p54 nrb complex to inhibit the activity of survivin gene promoter (10,11). YM155 has been demonstrated to inhibit the progression of certain neoplasms, such as prostate (10,12) and lung cancer (13,14). In the present study, we demonstrated that gemcitabine-resistant human TCC BFTC905 cells were sensitive to YM155 at very low concentrations, and the antineoplastic effects were more potent than cisplatin and/or gemcitabine.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells

et al. 2013

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Abstract. Survivin is overexpressed in transitional cell carcinoma (TCC), the most common type of bladder cancer. Previous reports demonstrated that knockdown of survivin by siRNA induced apoptosis of TCC cells. The present study evaluated the therapeutic effects of sepantronium bromide (YM155), a novel small molecule survivin inhibitor under clinical trials, on TCC cells in vitro. BFTC905, a grade III TCC cell line derived from a patient of blackfoot disease in Taiwan, was the most gemcitabine-resistant cell line when compared to BFTC909, TSGH8301 and T24 in cytotoxicity assay, resulting from upregulation of securin and bcl-2 after gemcitabine treatment. YM155 caused potent concentration-dependent cytotoxicity in 4 TCC cell lines (IC 50 s ≤20 nM), but exhibited no cytotoxicity in survivin-null primary human urothelial cells. For BFTC905 cells, addition of gemcitabine and/or cisplatin, the standard TCC chemotherapy regimen, to YM155 did not exert additive cytotoxic effects. Molecular analyses indicated that YM155 inhibited the proliferation of BFTC905 cells by increasing p27 kip1 , suppressing Ki-67, and inducing quiescence. In addition, YM155 elicited apoptosis manifested with DNA fragmentation through suppressing the expression of survivin, securin and bcl-2. Furthermore, YM155 induced autophagy in BFTC905 cells as autophagic inhibitor, 3-methyladenine, attenuated YM155-induced LC3B-II levels and reversed the cytotoxicity of YM155. mTOR inhibitors sirolimus and everolimus did not increase YM155-induced expression of LC3B-II nor augment YM155-induced cytotoxicity. These results indicate that YM155 exerts its lethal effect on BFTC905 cells via apoptotic and autophagic death pathways and suggest that YM155 may be a potential drug for the therapy of gemcitabine-resistant bladder cancer.

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Section: Discussioncontrasting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells

et al. 2013

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“…Multiple combination studies with YM155 were conducted with paclitaxel or docetaxel regimens based on the rationale that YM155 may be able to overcome taxane-mediated upregulation of survivin expression, which promotes drug resistance (44,(48)(49)(50). However, the lack of efficacy that was observed in these clinical studies may have been due to incomplete suppression of survivin levels in the tumors.…”

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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“…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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YM155, a novel survivin suppressant, enhances taxane-induced apoptosis and tumor regression in a human Calu 6 lung cancer xenograft model

Cited by 56 publications

References 31 publications

Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells

Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells

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

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

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