title: Combination treatment with arsenic trioxide and sulindac enhances apoptotic cell death in lung cancer cells via activation of oxidative stress and mitogen-activated protein kinases.
abstract: Arsenic trioxide (As2O3) has been introduced to the treatment of acute promyelocytic leukemia (APL), and has also been shown to induce apoptosis in a variety of solid tumor cell lines, including non-small cell lung cancer. However, the prohibitively high concentration required for the induction of apoptotic cell death in many solid tumor cells is unacceptable for clinical utilization due to the excessive toxicity associated with this dose. Sulindac is known to enhance the cellular responsiveness of tumors toward chemotherapeutic drugs. Herein, we demonstrated that combination treatment with As2O3 and sulindac resulted in a synergistic augmentation of cytotoxicity in H157 lung cancer cells, which was revealed by apoptotic induction as demonstrated by an increase in the sub-G0/G1 fraction. In addition, combination treatment with As2O3 and sulindac increased reactive oxygen species (ROS) and oxidative stress, as evidenced by the heme oxygenase-1 (HO-1) expression and mitogen-activated protein kinase (MAPK) phosphorylation. MAPK inhibitors blocked the induction of HO-1 by combination treatment. Inhibitors of p38 and JNK partially inhibited the augmented cell death whereas the ERK inhibitor showed poor inhibition. Combination treatment with As2O3 and sulindac induced oxidative DNA damage in a time-dependent fashion, which was evaluated by H2AX phosphorylation along with HO-1 induction.
authors.affiliation: Department of Internal Medicine, Institute of Wonkwang Medical Science, Wonkwang University, School of Medicine, Jeonbuk 570-749, South Korea.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Kim
authors.forename: Hye-Yeon
authors.initials: HY
authors.lastname: Jang
authors.forename: Heyok
authors.initials: H
authors.lastname: Shim
authors.forename: Kang-Kyoo
authors.initials: KK
authors.lastname: Lee
authors.forename: Hyang-Jeong
authors.initials: HJ
authors.lastname: Jo
authors.forename: Hwi-Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sei-Hoon
authors.initials: SH
authors.lastname: Yang
authors.forename: Eun-Taik
authors.initials: ET
authors.lastname: Jeong
authors.forename: Hak-Ryul
authors.initials: HR
authors.lastname: Kim
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage; D015153:Blotting, Western; D004249:DNA Damage / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010087:Oxides / Q000008:administration & dosage; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013467:Sulindac / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001152:Arsenicals; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D010087:Oxides; D017382:Reactive Oxygen Species; D013467:Sulindac; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide