title: 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.
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.
authors.affiliation: Department of Medical Education and Research, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kasukabe
authors.affiliation: Cancer Center, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Honma
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama 362-0806, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Okabe-Kado
authors.affiliation: The Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higuchi
authors.affiliation: The Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kato
authors.affiliation: Department of Medical Education and Research, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kumakura
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003514:Cyclohexylamines / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology*; D006027:Glycosides / Q000494:pharmacology; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010655:Phenylenediamines / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D000975:Antioxidants; D003514:Cyclohexylamines; D004224:Diterpenes; D006027:Glycosides; C000605940:ISIR-042; D017879:Isothiocyanates; D010655:Phenylenediamines; D011804:Quinolines; D017382:Reactive Oxygen Species; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C423222:cotylenin A; C573944:ferrostatin-1; C468548:quinoline-val-asp(OMe)-CH2-OPH; C058305:phenethyl isothiocyanate; D000111:Acetylcysteine