title: LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells.
abstract: Hypoxia‑inducible factor 1 (HIF‑1) activates the transcription of genes that act upon the adaptation of cancer cells to hypoxia. LW6, an HIF‑1 inhibitor, was hypothesized to improve resistance to cancer therapy in hypoxic tumors by inhibiting the accumulation of HIF‑1α. A clear anti‑tumor effect under low oxygen conditions would indicate that LW6 may be an improved treatment strategy for cancer in hypoxia. In the present study, the HIF‑1 inhibition potential of LW6 on the growth and apoptosis of A549 lung cancer cells in association with oxygen availability was evaluated. LW6 was observed to inhibit the expression of HIF‑1α induced by hypoxia in A549 cells at 20 mM, independently of the von Hippel‑Lindau protein. In addition, at this concentration, LW6 induced hypoxia‑selective apoptosis together with a reduction in the mitochondrial membrane potential. The intracellular reactive oxygen species levels increased in LW6‑treated hypoxic A549 cells and LW6 induced a hypoxia‑selective increase of mitochondrial O2•‑. In conclusion, LW6 inhibited the growth of hypoxic A549 cells by affecting the mitochondria. The inhibition of the mitochondrial respiratory chain is suggested as a potentially effective strategy to target apoptosis in cancer cells.
authors.affiliation: Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Hirose
authors.affiliation: Department of Radiological Life Sciences, Hirosaki University Graduate School of Health Sciences, Hirosaki, Aomori 036‑8564, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kashiwakura
authors.affiliation: Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Kawaguchi
authors.affiliation: Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan.
authors.forename: Yoshiomi
authors.initials: Y
authors.lastname: Hatayama
authors.affiliation: Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Akimoto
authors.affiliation: Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Narita
authors.affiliation: Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takai
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000083:Acetanilides; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000607696:LW6 compound; D017382:Reactive Oxygen Species; D000218:Adamantane