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YM155 and chrysin cooperatively suppress survivin expression in SMARCB1/INI1-deficient tumor cells

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Abstract

SMARCB1/INI1 deficiency is seen in several malignant tumors including malignant rhabdoid tumor (MRT), a highly aggressive pediatric malignancy. Loss of SMARCB1/INI1 function alters diverse oncogenic cellular signals, making it difficult to discover effective targeting therapy. By utilizing an in vitro drug screening system, effective therapeutic agents against SMARCB1/INI1-deficient tumors were explored in this study. In the in vitro drug sensitivity test, 80 agents with various actions were screened for their cytotoxicity in a panel of five SMARCB1/INI1-deficient tumor cell lines. The combination effect was screened based on the Bliss independent model. The growth-inhibitory effect was determined in both the conventional two-dimensional culture and the collagen-embedded three-dimensional culture system. Survivin expression after agent exposure was determined by Western blot analysis. All five cell lines were found to be sensitive to YM155, a selective survivin inhibitor. In the drug combination screening, YM155 showed additive to synergistic effects with various agents including chrysin. Chrysin enhanced YM155-induced apoptosis, but not mitochondrial depolarization upon exposure of SMARCB1/INI1-deficient tumor cells to the two agents for 6 h. YM155 and chrysin synergistically suppressed survivin expression, especially in TTN45 cells in which such suppression was observed as early as 6 h after exposure to the two agents. Survivin is suggested to be a therapeutic target in MRT and other SMARCB1/INI1-deficient tumors. Chrysin, a flavone that is widely distributed in plants, cooperatively suppressed survivin expression and enhanced the cytotoxicity of YM155.

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All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Funding

This work was supported by Kanagawa Children’s Medical Foundation; Kanagawa Prefectural Hospital Organization.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Kanagawa Children’s Medical Center, 2-138-4 Mutsukawa Minami-Ku, Yokohama, Japan

    Yuki Yoshino, Hiroaki Goto, Mieko Ito & Masakatsu Yanagimachi

  2. Department of Nutrition and Health, Sagami Women’s University, Sagamihara, Japan

    Yoshinori Tsurusaki

  3. Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Junko Takita

  4. Institute of Physiology and Medicine, Jobu University, Takasaki, Japan

    Yasuhide Hayashi

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  1. Yuki Yoshino
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  2. Hiroaki Goto
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  4. Yoshinori Tsurusaki
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  5. Junko Takita
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Contributions

All authors contributed to the study conception and design. Cell lines were established and maintained by HG, JT, and YH. Material preparation, data collection, and analysis were performed by YY, MI, YT, and MY. The first draft of the manuscript was written by YY and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hiroaki Goto.

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The authors declare that they do not have any conflicts of interest related to the presented study.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Kanagawa Children’s Medical Center (09/14/2017, No. 105-8).

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Supplementary Information

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12032_2022_1843_MOESM1_ESM.tif

Supplementary file1 (TIF 250 KB)—Supplemental Figure 1. In vitro drug sensitivity screening in a panel of SMARCB1/INI1-deficient cell lines. Cells were injected onto a 384-well plate, and after 1-day incubation, 80 agents belonging to several different classes at 4 serially diluted concentrations were loaded onto the wells. After 4 days’ incubation, cell viability in each well was measured using the CellTiter-Glo luminescent assay (Promega, Madison, WI, USA). Cell survival rates in agent-containing wells were expressed as ratios of live cell-derived luminescence compared to the mean luminescence value in 5 agent-free control wells. To compare agent sensitivity among the samples, the drug effect score (DES) was calculated for each agent as follows: DES = {(100 − % survival at 5–3 dilution)*ln(125) + (100 − % survival at 5–2 dilution)*ln(25) + (100 − % survival at 5–1 dilution)*ln(5) + (100 − % survival at no dilution)}/{ln(125) + ln(25) + ln(5) + 1}. A cell line was defined to be sensitive to the tested agent if its DES was larger than the reference DES (i.e., the mean DES when peripheral blood mononuclear cells from 5 healthy volunteers were tested in the same drug sensitivity test). In the heat map of Fig. 1, the number represents the DES of the tested agent at a particular concentration after subtracting the corresponding reference DES. A red box indicates high DES; the more intense the redness, the higher the DES. Topotecan (red arrow) and YM155 (red arrow) showed relatively high DES values in the 5 cell lines. The highest concentrations of agents used in the screening assay are shown in Supplemental Table 1.

12032_2022_1843_MOESM2_ESM.tif

Supplementary file2 (TIF 698 KB)—Supplemental Figure 2. Drug combination screening. The combination indexes between YM155 at 10 nM and agents with various modes of action at 4 serial dilutions are shown. A red box indicates that the combination index is less than 1.0, suggesting a synergistic effect.

12032_2022_1843_MOESM3_ESM.tif

Supplementary file3 (TIF 464 KB)—Supplemental Figure 3. Apoptotic change of nuclei after agent exposure. Cells were seeded onto a 24-well glass bottom plate with control medium, medium containing YM155 alone at 10 nM, medium containing chrysin alone at 4 μg/ml, or medium containing the combination of YM155 at 10 nM and chrysin at 4 μg/ml. After 48 h incubation, cellular nuclei were stained with NucBlue Live ReadyProbes Reagent (ThermoFisher Scientific, Waltham, MA) according to the manufacturer’s instructions. Nuclear blebbing indicating apoptotic change was observed upon incubation with YM155, but was not evident upon incubation with chrysin alone. (Original magnification: ×200).

12032_2022_1843_MOESM4_ESM.tif

Supplementary file4 (TIF 823 KB)—Supplemental Figure 4. Loss of mitochondrial transmembrane potential after agent exposure. Fluorescent microscopic pictures after JC-1 staining are shown. See Figure Legend 4 for details. (Original magnification: ×100).

Supplementary file5 (TIF 172 KB)

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Yoshino, Y., Goto, H., Ito, M. et al. YM155 and chrysin cooperatively suppress survivin expression in SMARCB1/INI1-deficient tumor cells. Med Oncol 39, 234 (2022). https://doi.org/10.1007/s12032-022-01843-4

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