Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
September-2015 Volume 12 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
September-2015 Volume 12 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

LW6, a hypoxia‑inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells

  • Authors:
    • Mariko Sato
    • Katsumi Hirose
    • Ikuo Kashiwakura
    • Masahiko Aoki
    • Hideo Kawaguchi
    • Yoshiomi Hatayama
    • Hiroyoshi Akimoto
    • Yuichiro Narita
    • Yoshihiro Takai
  • View Affiliations / Copyright

    Affiliations: Department of Radiology and Radiation Oncology, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036‑8562, Japan, Department of Radiological Life Sciences, Hirosaki University Graduate School of Health Sciences, Hirosaki, Aomori 036‑8564, Japan
    Copyright: © Sato et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
  • Pages: 3462-3468
    |
    Published online on: May 27, 2015
       https://doi.org/10.3892/mmr.2015.3862
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



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.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

The Editorial Board of the Cancer Statistics in Japan: Cancer Statistics in Japan 2012. Foundation for Promotion of Cancer Research; Tokyo, Japan: 2012

2 

Harris AL: Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer. 2:38–47. 2002. View Article : Google Scholar : PubMed/NCBI

3 

Ellis LM and Fidler IJ: Angiogenesis and metastasis. Eur J Cancer. 32A:2451–2460. 1996. View Article : Google Scholar : PubMed/NCBI

4 

Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL and Simons JW: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 59:5830–5835. 1999.PubMed/NCBI

5 

Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR and Dewhirst MW: Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 56:941–943. 1996.PubMed/NCBI

6 

Theodoropoulos VE, Lazaris AC, Sofras F, Gerzelis I, Tsoukala V, Ghikonti I, Manikas K and Kastriotis I: Hypoxia-inducible factor 1 alpha expression correlates with angiogenesis and unfavorable prognosis in bladder cancer. Eur Urol. 46:200–208. 2004. View Article : Google Scholar : PubMed/NCBI

7 

Sundfør K, Lyng H and Rofstad EK: Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix. Br J Cancer. 78:822–827. 1998. View Article : Google Scholar : PubMed/NCBI

8 

Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfør K, Rofstad EK and Mueller-Klieser W: High lactate levels predict likelihood of metastases, tumor recurrence and restricted patient survival in human cervical cancers. Cancer Res. 60:916–921. 2000.PubMed/NCBI

9 

Walenta S, Salameh A, Lyng H, Evensen JF, Mitze M, Rofstad EK and Mueller-Klieser W: Correlation of high lactate levels in head and neck tumors with incidence of metastasis. Am J Pathol. 150:409–415. 1997.PubMed/NCBI

10 

Pitson G, Fyles A, Milosevic M, Wylie J, Pintilie M and Hill R: Tumor size and oxygenation are independent predictors of nodal diseases in patients with cervix cancer. Int J Radiat Oncol Biol Phys. 51:699–703. 2001. View Article : Google Scholar : PubMed/NCBI

11 

Papandreou I, Cairns RA, Fontana L, Lim AL and Denko NC: HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3:187–197. 2006. View Article : Google Scholar : PubMed/NCBI

12 

Kim JW, Tchernyshyov I, Semenza GL and Dang CV: HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3:177–185. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Giaccia A, Siim BG and Johnson RS: HIF-1 as a target for drug development. Nat Rev Drug Discov. 2:803–811. 2003. View Article : Google Scholar : PubMed/NCBI

14 

Okamoto K, Ito D, Miyazaki K, Watanabe S, Tohyama O, Yokoi A, Ozawa Y, Asano M, Kawamura T, Yamane Y, et al: Microregional antitumor activity of a small-molecule hypoxia-inducible factor 1 inhibitor. Int J Mol Med. 29:541–549. 2012.PubMed/NCBI

15 

Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G and Powis G: Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther. 3:233–244. 2004.PubMed/NCBI

16 

Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS and Park JW: YC-1: A potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst. 95:516–525. 2003. View Article : Google Scholar : PubMed/NCBI

17 

Lee K, Kang JE, Park SK, Jin Y, Chung KS, Kim HM, Lee K, Kang MR, Lee MK, Song KB, et al: LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1alpha via upregulation of VHL in a colon cancer cell line. Biochem Pharmacol. 80:982–989. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV and Semenza GL: HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 11:407–420. 2007. View Article : Google Scholar : PubMed/NCBI

19 

Lee K, Ban HS, Naik R, Hong YS, Son S, Kim BK, Xia Y, Song KB, Lee HS and Won M: Identification of malate dehydrogenase 2 as a target protein of the HIF-1 inhibitor LW6 using chemical probes. Angew Chem Int Ed Engl. 52:10286–10289. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Liu Y, Fiskum G and Schubert D: Generation of reactive oxygen species by the mitochondrial electron transport chain. J Neurochem. 80:780–787. 2002. View Article : Google Scholar : PubMed/NCBI

21 

Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, et al: Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 394:485–490. 1998. View Article : Google Scholar : PubMed/NCBI

22 

Yeo EJ, Ryu JH, Chun YS, Cho YS, Jang IJ, Cho H, Kim J, Kim MS and Park JW: YC-1 induces S cell cycle arrest and apoptosis by activating checkpoint kinases. Cancer Res. 66:6345–6352. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Zhao Q, Du J, Gu H, Teng X, Zhang Q, Qin H and Liu N: Effects of YC-1 on hypoxia-inducible factor 1-driven transcription activity, cell proliferative vitality and apoptosis in hypoxic human pancreatic cancer cells. Pancreas. 34:242–247. 2007. View Article : Google Scholar : PubMed/NCBI

24 

Chen D, Li M, Luo J and Gu W: Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function. J Biol Chem. 278:13595–13598. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Hansson LO, Friedler A, Freund S, Rudiger S and Fersht AR: Two sequence motifs from HIF-1alpha bind to the DNA-binding site of p53. Proc Natl Acad Sci USA. 99:10305–10309. 2002. View Article : Google Scholar : PubMed/NCBI

26 

Kothari S, Cizeau J, McMillan-Ward E, Israels SJ, Bailes M, Ens K, Kirshenbaum LA and Gibson SB: BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF. Oncogene. 22:4734–4744. 2003. View Article : Google Scholar : PubMed/NCBI

27 

Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, Hakem R and Greenberg AH: BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol. 20:5454–5468. 2000. View Article : Google Scholar : PubMed/NCBI

28 

Akakura N, Kobayashi M, Horiuchi I, Suzuki A, Wang J, Chen J, Niizeki H, Kawamura Ki, Hosokawa M and Asaka M: Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 61:6548–6554. 2001.PubMed/NCBI

29 

Tait SW and Green DR: Mitochondria and cell death: Outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 11:621–632. 2010. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Sato M, Hirose K, Kashiwakura I, Aoki M, Kawaguchi H, Hatayama Y, Akimoto H, Narita Y and Takai Y: LW6, a hypoxia‑inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells. Mol Med Rep 12: 3462-3468, 2015.
APA
Sato, M., Hirose, K., Kashiwakura, I., Aoki, M., Kawaguchi, H., Hatayama, Y. ... Takai, Y. (2015). LW6, a hypoxia‑inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells. Molecular Medicine Reports, 12, 3462-3468. https://doi.org/10.3892/mmr.2015.3862
MLA
Sato, M., Hirose, K., Kashiwakura, I., Aoki, M., Kawaguchi, H., Hatayama, Y., Akimoto, H., Narita, Y., Takai, Y."LW6, a hypoxia‑inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells". Molecular Medicine Reports 12.3 (2015): 3462-3468.
Chicago
Sato, M., Hirose, K., Kashiwakura, I., Aoki, M., Kawaguchi, H., Hatayama, Y., Akimoto, H., Narita, Y., Takai, Y."LW6, a hypoxia‑inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells". Molecular Medicine Reports 12, no. 3 (2015): 3462-3468. https://doi.org/10.3892/mmr.2015.3862
Copy and paste a formatted citation
x
Spandidos Publications style
Sato M, Hirose K, Kashiwakura I, Aoki M, Kawaguchi H, Hatayama Y, Akimoto H, Narita Y and Takai Y: LW6, a hypoxia‑inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells. Mol Med Rep 12: 3462-3468, 2015.
APA
Sato, M., Hirose, K., Kashiwakura, I., Aoki, M., Kawaguchi, H., Hatayama, Y. ... Takai, Y. (2015). LW6, a hypoxia‑inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells. Molecular Medicine Reports, 12, 3462-3468. https://doi.org/10.3892/mmr.2015.3862
MLA
Sato, M., Hirose, K., Kashiwakura, I., Aoki, M., Kawaguchi, H., Hatayama, Y., Akimoto, H., Narita, Y., Takai, Y."LW6, a hypoxia‑inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells". Molecular Medicine Reports 12.3 (2015): 3462-3468.
Chicago
Sato, M., Hirose, K., Kashiwakura, I., Aoki, M., Kawaguchi, H., Hatayama, Y., Akimoto, H., Narita, Y., Takai, Y."LW6, a hypoxia‑inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells". Molecular Medicine Reports 12, no. 3 (2015): 3462-3468. https://doi.org/10.3892/mmr.2015.3862
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team