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Article

Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells

  • Authors:
    • Takashi Kasukabe
    • Yoshio Honma
    • Junko Okabe-Kado
    • Yusuke Higuchi
    • Nobuo Kato
    • Shunichi Kumakura
  • View Affiliations / Copyright

    Affiliations: Department of Medical Education and Research, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan, Cancer Center, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan, Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama 362-0806, Japan, The Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan
  • Pages: 968-976
    |
    Published online on: June 10, 2016
       https://doi.org/10.3892/or.2016.4867
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Abstract

The treatment of pancreatic cancer, one of the most aggressive gastrointestinal tract malignancies, with current chemotherapeutic drugs has had limited success due to its chemoresistance and poor prognosis. Therefore, the development of new drugs or effective combination therapies is urgently needed. Cotylenin A (CN-A) (a plant growth regulator) is a potent inducer of differentiation in myeloid leukemia cells and exhibits potent antitumor activities in several cancer cell lines. In the present study, we demonstrated that CN-A and phenethyl isothiocyanate (PEITC), an inducer of reactive oxygen species (ROS) and a dietary anticarcinogenic compound, synergistically inhibited the proliferation of MIAPaCa-2, PANC-1 and gemcitabine-resistant PANC-1 cells. A combined treatment with CN-A and PEITC also effectively inhibited the anchorage-independent growth of these cancer cells. The combined treatment with CN-A and PEITC strongly induced cell death within 1 day at concentrations at which CN-A or PEITC alone did not affect cell viability. A combined treatment with synthetic CN-A derivatives (ISIR-005 and ISIR-042) or fusicoccin J (CN-A-related natural product) and PEITC did not have synergistic effects on cell death. The combined treatment with CN-A and PEITC synergistically induced the generation of ROS. Antioxidants (N-acetylcysteine and trolox), ferroptosis inhibitors (ferrostatin-1 and liproxstatin), and the lysosomal iron chelator deferoxamine canceled the synergistic cell death. Apoptosis inhibitors (Z-VAD-FMK and Q-VD-OPH) and the necrosis inhibitor necrostatin-1s did not inhibit synergistic cell death. Autophagy inhibitors (3-metyladenine and chloroquine) partially prevented cell death. These results show that synergistic cell death induced by the combined treatment with CN-A and PEITC is mainly due to the induction of ferroptosis. Therefore, the combination of CN-A and PEITC has potential as a novel therapeutic strategy against pancreatic cancer.
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Copy and paste a formatted citation
Spandidos Publications style
Kasukabe T, Honma Y, Okabe-Kado J, Higuchi Y, Kato N and Kumakura S: Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells. Oncol Rep 36: 968-976, 2016.
APA
Kasukabe, T., Honma, Y., Okabe-Kado, J., Higuchi, Y., Kato, N., & Kumakura, S. (2016). Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells. Oncology Reports, 36, 968-976. https://doi.org/10.3892/or.2016.4867
MLA
Kasukabe, T., Honma, Y., Okabe-Kado, J., Higuchi, Y., Kato, N., Kumakura, S."Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells". Oncology Reports 36.2 (2016): 968-976.
Chicago
Kasukabe, T., Honma, Y., Okabe-Kado, J., Higuchi, Y., Kato, N., Kumakura, S."Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells". Oncology Reports 36, no. 2 (2016): 968-976. https://doi.org/10.3892/or.2016.4867
Copy and paste a formatted citation
x
Spandidos Publications style
Kasukabe T, Honma Y, Okabe-Kado J, Higuchi Y, Kato N and Kumakura S: Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells. Oncol Rep 36: 968-976, 2016.
APA
Kasukabe, T., Honma, Y., Okabe-Kado, J., Higuchi, Y., Kato, N., & Kumakura, S. (2016). Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells. Oncology Reports, 36, 968-976. https://doi.org/10.3892/or.2016.4867
MLA
Kasukabe, T., Honma, Y., Okabe-Kado, J., Higuchi, Y., Kato, N., Kumakura, S."Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells". Oncology Reports 36.2 (2016): 968-976.
Chicago
Kasukabe, T., Honma, Y., Okabe-Kado, J., Higuchi, Y., Kato, N., Kumakura, S."Combined treatment with cotylenin A and phenethyl isothiocyanate induces strong antitumor activity mainly through the induction of ferroptotic cell death in human pancreatic cancer cells". Oncology Reports 36, no. 2 (2016): 968-976. https://doi.org/10.3892/or.2016.4867
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