Population pharmacokinetic modeling of Sepantronium bromide (YM155), a small molecule survivin suppressant, in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma

Aoyama, Yumiko; Kaibara, Atsunori; Takada, Akitsugu; Nishimura, Tetsuya; Katashima, Masataka; Sawamoto, Taiji

doi:10.1007/s10637-012-9867-x

Cited by 17 publications

(16 citation statements)

References 18 publications

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“…This is in the range of therapeutically achievable plasma levels that were documented to reach about 50 nM. 20, 21, 22 Notably, animal models indicated that the YM155 concentrations in tumor tissues are likely to be higher than those found in the plasma. 3, 23 Previously, YM155 IC50 values were reported to range from 3.2 to 11 nM in melanoma cells 24 and from 2 to 50 nM in multiple myeloma cells.…”

Section: Discussionmentioning

confidence: 88%

Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance

Voges¹,

Michaelis²,

Rothweiler³

et al. 2016

Cell Death Dis

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Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug's mechanism of action.

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Section: Discussionmentioning

confidence: 88%

Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance

Voges¹,

Michaelis²,

Rothweiler³

et al. 2016

Cell Death Dis

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“…Several phase I and II clinical trials ofYM155 combined with chemotherapeutic agents have been conducted in patients with breast, prostate, non-small-cell lung cancer, non–Hodgkin lymphoma, and colorectal cancer(46,47). Nonetheless, the portfolio of survivin antagonists or suppressors available for clinical testing, particularly in SCCHN, is very limited.…”

Section: Discussionmentioning

confidence: 99%

Honokiol Radiosensitizes Squamous Cell Carcinoma of the Head and Neck by Downregulation of Survivin

Wang

Beitler

Huang

et al. 2018

Clinical Cancer Research

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Purpose Previous studies revealed diverging results regarding the role of survivin in squamous cell carcinoma of the head and neck (SCCHN).This study aimed to evaluate the clinical significance of survivin expression in SCCHN; the function of survivin in DNA damage repair following ionizing radiationtherapy (RT) in SCCHN cells; and the potential of honokiol to enhance RT through downregulation of survivin. Experimental Design Expression of survivin in SCCHN patient primary tumor tissues (n=100) was analyzed and correlated with clinical parameters. SCCHN cell lines were used to evaluate the function of survivin and the effects of honokiol on survivin expression in vitro and in vivo. Results Overexpression of survivin was significantly associated with lymph nodes metastatic status (p=0.025), worse overall survival (OS) and disease free survival (DFS) in patients receiving RT (n=65, OS: p=0.024, DFS: p=0.006) and in all patients with SCCHN (n=100, OS: p=0.002, DFS: p=0.003). In SCCHN cells, depletion of survivin led to increased DNA damage and cell death following RT, whereas overexpression of survivin increased clonogenic survival. RT induced nuclear accumulation of survivin and its molecular interaction with γ-H2AX and DNA-PKCs. Survivin specifically bound to DNA DSB sites induced by I-SceI endonuclease. Honokiol (which downregulates survivin expression) in combination with RT significantly augmented cytotoxicity in SCCHN cells with acquired radioresistance and inhibited growth in SCCHN xenograft tumors. Conclusions Survivin is a negative prognostic factor and is involved in DNA damage repair induced by RT. Targeting survivin using honokiol in combination with RT may provide novel therapeutic opportunities.

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“…YM155 has entered a few early stage clinical trials for the treatment of advanced cancers. The preliminary results have shown a potent anti-tumor growth activity (11, 12, 32, 33). However, YM155 has yet to be fully tested in human pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Inhibitor YM155-Mediated Activation of Death Receptor 5 Is Crucial for Chemotherapy-Induced Apoptosis in Pancreatic Carcinoma

Zhao

Puszyk

et al. 2015

Molecular Cancer Therapeutics

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Despite much effort, pancreatic cancer survival rates are still dismally low. Novel therapeutics may hold the key to improving survival. YM155 is a small molecule inhibitor which has shown anti-tumor activity in a number of cancers by reducing the expression of survivin. The aim of our study is to understand the mechanisms by which YM155 functions in pancreatic cancer cells. We established the anti-tumor effect of YM155 with in vitro studies in the cultured cells, and in vivo studies using a mouse xenograft model. Our data demonstrated that YM155 reduced the expression of survivin; however down-regulation of survivin itself is insufficient to induce apoptosis in pancreatic cancer cells. We showed for the first time that treatment with YM155 increased death receptor 5 (DR5) expression in pancreatic cancer cells. We found that YM155 induced apoptosis by broad-spectrum inhibition of IAP family member proteins (e.g. CIAP1/2 and FLIP) and induced pro-apoptotic Bak protein up-regulation and activation; the anti-tumor effect of YM155 treatment with either the DR5 agonist lexatumumab or gemcitabine on pancreatic cancer cells was synergistic. Our data also revealed that YM155 inhibit tumor growth in vivo, whilst had no apparent toxicity to the non-cancerous human pancreatic ductal epithelial cell line (HPDE). Together, these findings suggest that YM155 could be a novel therapeutic agent for pancreatic cancer.

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Population pharmacokinetic modeling of Sepantronium bromide (YM155), a small molecule survivin suppressant, in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma

Cited by 17 publications

References 18 publications

Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance

Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance

Honokiol Radiosensitizes Squamous Cell Carcinoma of the Head and Neck by Downregulation of Survivin

Small Molecule Inhibitor YM155-Mediated Activation of Death Receptor 5 Is Crucial for Chemotherapy-Induced Apoptosis in Pancreatic Carcinoma

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