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Albendazole inhibits HIF-1α-dependent glycolysis and VEGF expression in non-small cell lung cancer cells

Abstract

Albendazole (ABZ) has an anti-tumor ability and inhibits HIF-1α activity. HIF-1α is associated with glycolysis and vascular endothelial cell growth factor (VEGF) expression, which plays an important role in cancer progression. These clues indicate that ABZ exerts an anti-cancer effect by regulating glycolysis and VEGF expression. The aim of this study is to clarify the effects of ABZ on non-small cell lung cancer (NSCLC) cells and explore the underlying molecular mechanisms. The expression levels of HIF-1α and VEGF were detected using western blot analysis, and the effect of ABZ on glycolysis was evaluated by measuring the relative activities of hexokinase (HK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) and detecting the production of lactate in A549 and H1299 cells. The results showed that ABZ decreased the expression levels of HIF-1α and VEGF and suppressed glycolysis in under hypoxia, but not normoxic condition. Inhibiting HIF-1α also suppressed glycolysis and VEGF expression. Additionally, ABZ inhibited the volume and weight, decreased the relative activities of HK, PK, and LDH, and reduced the levels of HIF-1α and VEGF of A549 xenografts in mouse models. In conclusion, ABZ inhibited growth of NSCLC cells by suppressing HIF-1α-dependent glycolysis and VEGF expression.

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References

  1. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J (2016) Cancer statistics in China, 2015. CA Cancer J Clin 66(2):115–132

    Article  PubMed  Google Scholar 

  2. Siegel R, Miller K, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29

    Article  PubMed  Google Scholar 

  3. Horton J (2002) Albendazole: a broad spectrum anthelminthic for treatment of individuals and populations. Curr Opin Infect Dis 15(6):599–608

    CAS  Article  PubMed  Google Scholar 

  4. Lacey E (1990) Mode of action of benzimidazoles. Parasitol Today 6(4):112–115

    CAS  Article  PubMed  Google Scholar 

  5. Lacey E, Watson TR (1985) Activity of benzimidazole carbamates against L1210 mouse leukaemia cells: correlation with in vitro tubulin polymerization assay. Biochem Pharmacol 34(19):3603–3605

    CAS  Article  PubMed  Google Scholar 

  6. Pourgholami M, Woon L, Almajd R, Akhter J, Bowery P, Morris D (2001) In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by albendazole. Cancer Lett 165(1):43–49

    CAS  Article  PubMed  Google Scholar 

  7. Pourgholami MH, Akhter J, Wang L, Lu Y, Morris DL (2005) Antitumor activity of albendazole against the human colorectal cancer cell line HT-29: in vitro and in a xenograft model of peritoneal carcinomatosis. Cancer Chemother Pharmacol 55(5):425–432

    CAS  Article  PubMed  Google Scholar 

  8. Pourgholami MH, Szwajcer M, Chin M, Liauw W, Seef J, Galettis P, Morris DL, Links M (2010) Phase I clinical trial to determine maximum tolerated dose of oral albendazole in patients with advanced cancer. Cancer Chemother Pharmacol 65(3):597–605

    CAS  Article  PubMed  Google Scholar 

  9. Kim JW, Dang CV (2006) Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res 66(18):8927–8930

    CAS  Article  PubMed  Google Scholar 

  10. Alfarouk KO, Muddathir AK, Shayoub ME (2011) Tumor acidity as evolutionary spite. Cancers 3(1):408–414

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11(2):85–95

    CAS  Article  PubMed  Google Scholar 

  12. Semenza GL (2010) HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20(1):51–56

    CAS  Article  PubMed  Google Scholar 

  13. Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8(9):705–713

    CAS  Article  PubMed  Google Scholar 

  14. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ (2001) Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292(5516):468–472

    CAS  Article  PubMed  Google Scholar 

  15. Ahluwalia A, S Tarnawski A (2012) Critical role of hypoxia sensor-HIF-1α in VEGF gene activation. Implications for angiogenesis and tissue injury healing. Curr Med Chem 19(1):90–97

    CAS  Article  PubMed  Google Scholar 

  16. Cathcart MC, Gately K, Cummins R, Drakeford C, Kay EW, O’Byrne KJ, Pidgeon GP (2014) Thromboxane synthase expression and correlation with VEGF and angiogenesis in non-small cell lung cancer. Biochim Biophys Acta 1842(5):747–755

    CAS  Article  PubMed  Google Scholar 

  17. Alevizakos M, Kaltsas S, Syrigos KN (2013) The VEGF pathway in lung cancer. Cancer Chemother Pharmacol 72(6):1169–1181

    CAS  Article  PubMed  Google Scholar 

  18. Okumura H, Uchikado Y, Setoyama T, Matsumoto M, Owaki T, Ishigami S, Natsugoe S (2014) Biomarkers for predicting the response of esophageal squamous cell carcinoma to neoadjuvant chemoradiation therapy. Surg Today 44(3):421–428

    CAS  Article  PubMed  Google Scholar 

  19. Shiau AL, Shen YT, Hsieh JL, Wu CL, Lee CH (2014) Scutellaria barbata inhibits angiogenesis through downregulation of HIF-1 α in lung tumor. Environ Toxicol 29(4):363–370

    CAS  Article  PubMed  Google Scholar 

  20. Ahn GO, Seita J, Hong BJ, Kim YE, Bok S, Lee CJ, Kim KS, Lee JC, Leeper NJ, Cooke JP, Kim HJ, Kim IH, Weissman IL, Brown JM (2014) Transcriptional activation of hypoxia-inducible factor-1 (HIF-1) in myeloid cells promotes angiogenesis through VEGF and S100A8. Proc Natl Acad Sci USA 111(7):2698–2703

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Noorani L, Stenzel M, Liang R, Pourgholami MH, Morris DL (2015) Albumin nanoparticles increase the anticancer efficacy of albendazole in ovarian cancer xenograft model. J Nanobiotechnol 13(1):25

    Article  Google Scholar 

  22. Patel K, Doudican NA, Schiff PB, Orlow SJ (2011) Albendazole sensitizes cancer cells to ionizing radiation. Radiat Oncol 6:160

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Liu JS, Liu J (2013) Effect of Albendazole on proliferation and apoptosis of human colon carcinoma SW480 cells and Bcl-2 expression. Chin J Biol 26(5):685–689

    CAS  Google Scholar 

  24. Clara CA, Marie SK, Almeida JRW, Wakamatsu A, Oba-Shinjo SM, Uno M, Neville M, Rosemberg S (2014) Angiogenesis and expression of PDGF-C, VEGF, CD105 and HIF-1α in human glioblastoma. Neuropathology 34(4):343–352

    CAS  PubMed  Google Scholar 

  25. Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K (2011) VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med 17(7):347–362

    CAS  Article  PubMed  Google Scholar 

  26. Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, Kim MK, Kim YG, Jang JY, Kim CW (2013) Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS ONE 8(12):e84256

    Article  PubMed  PubMed Central  Google Scholar 

  27. Noorani L, Stenzel M, Liang R, Pourgholami MH, Morris DL (2015) Albumin nanoparticles increase the anticancer efficacy of albendazole in ovarian cancer xenograft model. J Nanobiotechnology 13:25

    Article  PubMed  PubMed Central  Google Scholar 

  28. Pourgholami MH, Cai ZY, Badar S, Wangoo K, Poruchynsky MS, Morris DL (2010) Potent inhibition of tumoral hypoxia-inducible factor 1α by albendazole. BMC Cancer 10(1):143

    Article  PubMed  PubMed Central  Google Scholar 

  29. Pourgholami MH, Cai ZY, Lu Y, Wang L, Morris DL (2006) Albendazole: a potent inhibitor of vascular endothelial growth factor and malignant ascites formation in OVCAR-3 tumor-bearing nude mice. Clin Cancer Res 12(6):1928–1935

    Article  PubMed  Google Scholar 

  30. Giatromanolaki A, Koukourakis MI, Sivridis E, Turley H, Talks K, Pezzella F, Gatter KC, Harris AL (2001) Relation of hypoxia inducible factor 1α and 2α in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival[J]. Br J Cancer 85(6):881–890

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Guo M, Song L-P, Jiang Y, Liu W, Yu Y, Chen G-Q (2006) Hypoxia-mimetic agents desferrioxamine and cobalt chloride induce leukemic cell apoptosis through different hypoxia-inducible factor-1α independent mechanisms. Apoptosis 11(1):67–77

    CAS  Article  PubMed  Google Scholar 

  32. Borcar A, Menze MA, Toner M, Hand SC (2013) Metabolic preconditioning of mammalian cells: mimetic agents for hypoxia lack fidelity in promoting phosphorylation of pyruvate dehydrogenase. Cell Tissue Res 351(1):99–106

    CAS  Article  PubMed  Google Scholar 

  33. Koh MY, Spivak-Kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL, Powis G (2008) Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α. Mol Cancer Ther 7(1):90–100

    CAS  Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  35. Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145(5):732–744

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Luo W, Semenza GL (2011) Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget 2(7):551–556

    Article  PubMed  PubMed Central  Google Scholar 

  37. Sanchez W, McGee S, Connor T, Mottram B, Wilkinson A, Whitehead J, Vuckovic S, Catley L (2013) Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib. Brit. J Cancer 108(8):1624–1633

    CAS  Article  Google Scholar 

  38. Zhang C, Liu J, Wu R, Liang Y, Lin M, Liu J, Chan CS, Hu W, Feng Z (2014) Tumor suppressor p53 negatively regulates glycolysis stimulated by hypoxia through its target RRAD. Oncotarget 5(14):5535–5546

    Article  PubMed  PubMed Central  Google Scholar 

  39. Su J, Chen X, Kanekura T (2009) A CD147-targeting siRNA inhibits the proliferation, invasiveness, and VEGF production of human malignant melanoma cells by down-regulating glycolysis. Cancer Lett 273(1):140–147

    CAS  Article  PubMed  Google Scholar 

  40. Wang J, Qi H, Diao Z, Zheng X, Li X, Ma S, Ji A, Yin C (2010) An outbreak of angiostrongyliasis cantonensis in Beijing. J Parasitol 96(2):377–381

    Article  PubMed  Google Scholar 

  41. Vinaud MC, Ferreira CS, Junior RdSL, Bezerra JCB (2008) Taenia crassiceps: energetic and respiratory metabolism from cysticerci exposed to praziquantel and albendazole in vitro. Exp Parasitol 120(3):221–226

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank all the members in our department for their help in experiment methods suggestion and data collection.

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Correspondence to Fang Zhou.

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Zhou, F., Du, J. & Wang, J. Albendazole inhibits HIF-1α-dependent glycolysis and VEGF expression in non-small cell lung cancer cells. Mol Cell Biochem 428, 171–178 (2017). https://doi.org/10.1007/s11010-016-2927-3

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  • DOI: https://doi.org/10.1007/s11010-016-2927-3

Keywords

  • Albendazole
  • HIF-1α
  • Glycolysis
  • VEGF
  • Non-small cell lung cancer