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
| Autor: | Yusuke Higuchi, Yoshio Honma, Shunichi Kumakura, Junko Okabe-Kado, Takashi Kasukabe, Nobuo Kato |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Phenethyl isothiocyanate Cell Survival Cell Antineoplastic Agents Apoptosis Phenylenediamines Pharmacology Antioxidants Amino Acid Chloromethyl Ketones 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Isothiocyanates Cell Line Tumor Humans Medicine Glycosides Viability assay Cell Proliferation Cyclohexylamines Cell Death business.industry Autophagy General Medicine Cell cycle Acetylcysteine Pancreatic Neoplasms 030104 developmental biology medicine.anatomical_structure Oncology chemistry 030220 oncology & carcinogenesis Cancer cell Quinolines Diterpenes Reactive Oxygen Species business |
| Zdroj: | Oncology Reports. 36:968-976 |
| ISSN: | 1791-2431 1021-335X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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