Open Access

Tranilast enhances the effect of anticancer agents in osteosarcoma

  • Authors:
    • Takayuki Nakashima
    • Satoshi Nagano
    • Takao Setoguchi
    • Hiromi Sasaki
    • Yoshinobu Saitoh
    • Shingo Maeda
    • Setsuro Komiya
    • Noboru Taniguchi
  • View Affiliations

  • Published online on: May 6, 2019     https://doi.org/10.3892/or.2019.7150
  • Pages: 176-188
  • Copyright: © Nakashima et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Tranilast [N‑(3',4'‑dimethoxycinnamoyl)‑anthranilic acid], initially developed as an antiallergic drug, also exhibits a growth inhibitory effect on various types of cancer. Osteosarcoma is treated mainly with high‑dose methotrexate, doxorubicin, cisplatin and ifosfamide; however, 20‑30% of patients cannot be cured of metastatic disease. We investigated whether tranilast enhances the anticancer effects of chemotherapeutic drugs and analyzed its mechanism of action in osteosarcomas. Tranilast inhibited proliferation of HOS, 143B, U2OS and MG‑63 osteosarcoma cells in a dose‑dependent manner, as well as enhancing the effects of cisplatin and doxorubicin. The average combination index at effect levels for tranilast in combination with cisplatin was 0.57 in HOS, 0.4 in 143B, 0.39 in U2OS and 0.51 in MG‑63 cells. Tranilast and cisplatin synergistically inhibited the viability of osteosarcoma cells. In flow cytometric analysis, although tranilast alone did not induce significant apoptosis, the combination of tranilast and cisplatin induced early and late apoptotic cell death. Expression of cleaved caspase‑3, cleaved poly(ADP‑ribose) polymerase and p‑H2AX was enhanced by tranilast in combination with cisplatin. Tranilast alone increased expression of p21 and Bim protein in a dose‑dependent manner. Cell cycle analysis using flow cytometry demonstrated that the combination of tranilast and cisplatin increased the number of cells in the G2/M phase. Compared with cisplatin alone, the combination increased levels of phospho‑cyclin‑dependent kinase 1 (Y15). In the 143B xenograft model, tumor growth was significantly inhibited by combined tranilast and cisplatin compared with the controls, whereas cisplatin alone did not significantly inhibit tumor growth. In conclusion, tranilast has a cytostatic effect on osteosarcoma cells and enhances the effect of anticancer drugs, especially cisplatin. Enhanced sensitivity to cisplatin was mediated by increased apoptosis through G2/M arrest. Since tranilast has been clinically approved and has few adverse effects, clinical trials of osteosarcoma chemotherapy in combination with tranilast are expected.
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July-2019
Volume 42 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Nakashima T, Nagano S, Setoguchi T, Sasaki H, Saitoh Y, Maeda S, Komiya S and Taniguchi N: Tranilast enhances the effect of anticancer agents in osteosarcoma. Oncol Rep 42: 176-188, 2019
APA
Nakashima, T., Nagano, S., Setoguchi, T., Sasaki, H., Saitoh, Y., Maeda, S. ... Taniguchi, N. (2019). Tranilast enhances the effect of anticancer agents in osteosarcoma. Oncology Reports, 42, 176-188. https://doi.org/10.3892/or.2019.7150
MLA
Nakashima, T., Nagano, S., Setoguchi, T., Sasaki, H., Saitoh, Y., Maeda, S., Komiya, S., Taniguchi, N."Tranilast enhances the effect of anticancer agents in osteosarcoma". Oncology Reports 42.1 (2019): 176-188.
Chicago
Nakashima, T., Nagano, S., Setoguchi, T., Sasaki, H., Saitoh, Y., Maeda, S., Komiya, S., Taniguchi, N."Tranilast enhances the effect of anticancer agents in osteosarcoma". Oncology Reports 42, no. 1 (2019): 176-188. https://doi.org/10.3892/or.2019.7150