Apoptosis

, Volume 17, Issue 10, pp 1120–1130 | Cite as

Vinpocetine inhibits breast cancer cells growth in vitro and in vivo

  • Er-Wen Huang
  • Sheng-Jiang Xue
  • Zheng Zhang
  • Jia-Guo Zhou
  • Yong-Yuan Guan
  • Yong-Bo Tang
Original Paper

Abstract

Vinpocetine is a clinically used drug for cerebrovascular disorders as well as age-related memory impairment. Of note, vinpocetine has been recently identified as a novel anti-inflammatory agent; however, its effects on cancer cells remain to be investigated. In the present study, we found that vinpocetine potently inhibited proliferation of multiple types of human breast cancer cells by arresting cell cycle at G0/G1 phase. It was also revealed that vinpocetine induced cell apoptosis via mitochondria-dependent pathway. Moreover, vinpocetine impaired the migration of the strongly metastatic cell MDA-MB-231. In xenograft model of human breast cancer in nude mice, both systemic and local administration of vinpocetine significantly suppressed the tumor growth without observed toxicity. Interestingly, vinpocetine markedly attenuated the activation of Akt and signal transducer and activator of transcription factor 3 (STAT3), but had no effects on MAP kinases pathways. Collectively, the data suggest that vinpocetine possesses significant yet previously unknown antitumor properties that may be utilized for the treatment of breast cancer.

Keywords

Vinpocetine Breast cancer Proliferation Apoptosis STAT3 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No.30900530), Doctoral Fund of Ministry of Education (for young teachers) of China (No.20090171120055); the Fundamental Research Funds for the Central Universities (No.50000-3161020).

References

  1. 1.
    Liu L, Zhang J, Wu AH, Pike MC, Deapen D (2012) Invasive breast cancer incidence trends by detailed race/ethnicity and age. Int J Cancer 130:395–404PubMedCrossRefGoogle Scholar
  2. 2.
    DeSantis C, Siegel R, Bandi P, Jemal A (2011) Breast cancer statistics, 2011. CA Cancer J Clin 61:409–418PubMedCrossRefGoogle Scholar
  3. 3.
    Smigal C, Jemal A, Ward E et al (2006) Trends in breast cancer by race and ethnicity: update 2006. CA Cancer J Clin 56:168–183PubMedCrossRefGoogle Scholar
  4. 4.
    Rochefort H (1987) Nonsteroidal antiestrogens are estrogen-receptor-targeted growth inhibitors that can act in the absence of estrogens. Horm Res 28:196–201PubMedCrossRefGoogle Scholar
  5. 5.
    Osborne CK (1998) Steroid hormone receptors in breast cancer management. Breast Cancer Res Treat 51:227–238PubMedCrossRefGoogle Scholar
  6. 6.
    Stacey SN, Sulem P, Jonasdottir A et al (2011) A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nat Genet 43:1098–1103PubMedCrossRefGoogle Scholar
  7. 7.
    Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR (2008) Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132:363–374PubMedCrossRefGoogle Scholar
  8. 8.
    Su F, Viros A, Milagre C et al (2012) RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366:207–215PubMedCrossRefGoogle Scholar
  9. 9.
    Garcia R, Bowman TL, Niu G et al (2001) Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20:2499–2513PubMedCrossRefGoogle Scholar
  10. 10.
    Szilagyi G, Nagy Z, Balkay L et al (2005) Effects of vinpocetine on the redistribution of cerebral blood flow and glucose metabolism in chronic ischemic stroke patients: a PET study. J Neurol Sci 229–230:275–284PubMedCrossRefGoogle Scholar
  11. 11.
    Dezsi L, Kis-Varga I, Nagy J, Komlodi Z, Karpati E (2002) Neuroprotective effects of vinpocetine in vivo and in vitro. Apovincaminic acid derivatives as potential therapeutic tools in ischemic stroke. Acta Pharm Hung 72:84–91PubMedGoogle Scholar
  12. 12.
    Bagoly E, Feher G, Szapary L (2007) The role of vinpocetine in the treatment of cerebrovascular diseases based in human studies. Orv Hetil 148:1353–1358PubMedCrossRefGoogle Scholar
  13. 13.
    Hagiwara M, Endo T, Hidaka H (1984) Effects of vinpocetine on cyclic nucleotide metabolism in vascular smooth muscle. Biochem Pharmacol 33:453–457PubMedCrossRefGoogle Scholar
  14. 14.
    Truss MC, Uckert S, Stief CG, Forssmann WG, Jonas U (1996) Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle. II. Effect of various PDE inhibitors on smooth muscle tone and cyclic nucleotide levels in vitro. Urol Res 24:129–134PubMedCrossRefGoogle Scholar
  15. 15.
    Sitges M, Galvan E, Nekrassov V (2005) Vinpocetine blockade of sodium channels inhibits the rise in sodium and calcium induced by 4-aminopyridine in synaptosomes. Neurochem Int 46:533–540PubMedCrossRefGoogle Scholar
  16. 16.
    Bonoczk P, Gulyas B, Adam-Vizi V et al (2000) Role of sodium channel inhibition in neuroprotection: effect of vinpocetine. Brain Res Bull 53:245–254PubMedCrossRefGoogle Scholar
  17. 17.
    Jeon KI, Xu X, Aizawa T et al (2010) Vinpocetine inhibits NF-kappaB-dependent inflammation via an IKK-dependent but PDE-independent mechanism. Proc Natl Acad Sci USA 107:9795–9800PubMedCrossRefGoogle Scholar
  18. 18.
    Nagel DJ, Aizawa T, Jeon KI et al (2006) Role of nuclear Ca2+/calmodulin-stimulated phosphodiesterase 1A in vascular smooth muscle cell growth and survival. Circ Res 98:777–784PubMedCrossRefGoogle Scholar
  19. 19.
    Tang YB, Liu YJ, Zhou JG, Wang GL, Qiu QY, Guan YY (2008) Silence of ClC-3 chloride channel inhibits cell proliferation and the cell cycle via G/S phase arrest in rat basilar arterial smooth muscle cells. Cell Prolif 41:775–785PubMedCrossRefGoogle Scholar
  20. 20.
    Li SY, Wang XG, Ma MM et al (2012) Ginsenoside-Rd potentiates apoptosis induced by hydrogen peroxide in basilar artery smooth muscle cells through the mitochondrial pathway. Apoptosis 17:113–120PubMedCrossRefGoogle Scholar
  21. 21.
    Shi XL, Wang GL, Zhang Z et al (2007) Alteration of volume-regulated chloride movement in rat cerebrovascular smooth muscle cells during hypertension. Hypertension 49:1371–1377PubMedCrossRefGoogle Scholar
  22. 22.
    Terradillos O, Montessuit S, Huang DC, Martinou JC (2002) Direct addition of BimL to mitochondria does not lead to cytochrome c release. FEBS Lett 522:29–34PubMedCrossRefGoogle Scholar
  23. 23.
    Wang GL, Wang XR, Lin MJ, He H, Lan XJ, Guan YY (2002) Deficiency in ClC-3 chloride channels prevents rat aortic smooth muscle cell proliferation. Circ Res 91:E28–E32PubMedCrossRefGoogle Scholar
  24. 24.
    Dimco G, Knight RA, Latchman DS, Stephanou A (2010) STAT1 interacts directly with cyclin D1/Cdk4 and mediates cell cycle arrest. Cell Cycle 9:4638–4649PubMedCrossRefGoogle Scholar
  25. 25.
    Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL (1997) Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem 272:10882–10894PubMedCrossRefGoogle Scholar
  26. 26.
    Nakayama K, Ishida N, Shirane M et al (1996) Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85:707–720PubMedCrossRefGoogle Scholar
  27. 27.
    Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell 147:742–758PubMedCrossRefGoogle Scholar
  28. 28.
    Sen B, Saigal B, Parikh N, Gallick G, Johnson FM (2009) Sustained Src inhibition results in signal transducer and activator of transcription 3 (STAT3) activation and cancer cell survival via altered Janus-activated kinase-STAT3 binding. Cancer Res 69:1958–1965PubMedCrossRefGoogle Scholar
  29. 29.
    Badache A, Hynes NE (2001) Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Res 61:383–391PubMedGoogle Scholar
  30. 30.
    Constantinescu SN, Girardot M, Pecquet C (2008) Mining for JAK-STAT mutations in cancer. Trends Biochem Sci 33:122–131PubMedCrossRefGoogle Scholar
  31. 31.
    Garcia R, Yu CL, Hudnall A et al (1997) Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. Cell Growth Differ 8:1267–1276PubMedGoogle Scholar
  32. 32.
    Song L, Turkson J, Karras JG, Jove R, Haura EB (2003) Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 22:4150–4165PubMedCrossRefGoogle Scholar
  33. 33.
    Ferrajoli A, Faderl S, Ravandi F, Estrov Z (2006) The JAK-STAT pathway: a therapeutic target in hematological malignancies. Curr Cancer Drug Targets 6:671–679PubMedCrossRefGoogle Scholar
  34. 34.
    Buettner R, Mora LB, Jove R (2002) Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res 8:945–954PubMedGoogle Scholar
  35. 35.
    Turkson J (2004) STAT proteins as novel targets for cancer drug discovery. Expert Opin Ther Targets 8:409–422PubMedCrossRefGoogle Scholar
  36. 36.
    Amiri A, Noei F, Jeganathan S, Kulkarni G, Pinke DE, Lee JM (2007) eEF1A2 activates Akt and stimulates Akt-dependent actin remodeling, invasion and migration. Oncogene 26:3027–3040PubMedCrossRefGoogle Scholar
  37. 37.
    Li Z, Qi CF, Shin DM et al (2010) Eef1a2 promotes cell growth, inhibits apoptosis and activates JAK/STAT and AKT signaling in mouse plasmacytomas. PLoS One 5:e10755PubMedCrossRefGoogle Scholar
  38. 38.
    Ahn HS, Crim W, Pitts B, Sybertz EJ (1992) Calcium-calmodulin-stimulated and cyclic-GMP-specific phosphodiesterases. Tissue distribution, drug sensitivity, and regulation of cyclic GMP levels. Adv Second Messenger Phosphoprot Res 25:271–288Google Scholar
  39. 39.
    Kaneko S, Takahashi H, Satoh M (1990) The use of Xenopus oocytes to evaluate drugs affecting brain Ca2+ channels: effects of bifemelane and several nootropic agents. Eur J Pharmacol 189:51–58PubMedCrossRefGoogle Scholar
  40. 40.
    Erdo SA, Molnar P, Lakics V, Bence JZ, Tomoskozi Z (1996) Vincamine and vincanol are potent blockers of voltage-gated Na+channels. Eur J Pharmacol 314:69–73PubMedCrossRefGoogle Scholar
  41. 41.
    Dunkern TR, Hatzelmann A (2007) Characterization of inhibitors of phosphodiesterase 1C on a human cellular system. FEBS J 274:4812–4824PubMedCrossRefGoogle Scholar
  42. 42.
    Savai R, Pullamsetti SS, Banat GA et al (2010) Targeting cancer with phosphodiesterase inhibitors. Expert Opin Investig Drugs 19:117–131PubMedCrossRefGoogle Scholar
  43. 43.
    Sengupta R, Sun T, Warrington NM, Rubin JB (2011) Treating brain tumors with PDE4 inhibitors. Trends Pharmacol Sci 32:337–344PubMedCrossRefGoogle Scholar
  44. 44.
    Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444PubMedCrossRefGoogle Scholar
  45. 45.
    de Visser KE, Korets LV, Coussens LM (2005) De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7:411–423PubMedCrossRefGoogle Scholar
  46. 46.
    Rebouissou S, Amessou M, Couchy G et al (2009) Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457:200–204PubMedCrossRefGoogle Scholar
  47. 47.
    Huber MA, Azoitei N, Baumann B et al (2004) NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 114:569–581PubMedGoogle Scholar
  48. 48.
    Luo JL, Tan W, Ricono JM et al (2007) Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature 446:690–694PubMedCrossRefGoogle Scholar
  49. 49.
    Mantovani A (2010) Molecular pathways linking inflammation and cancer. Curr Mol Med 10:369–373PubMedCrossRefGoogle Scholar
  50. 50.
    Medina AE (2010) Vinpocetine as a potent antiinflammatory agent. Proc Natl Acad Sci USA 107:9921–9922PubMedCrossRefGoogle Scholar
  51. 51.
    Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441:431–436PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Er-Wen Huang
    • 1
  • Sheng-Jiang Xue
    • 1
    • 2
  • Zheng Zhang
    • 1
  • Jia-Guo Zhou
    • 1
  • Yong-Yuan Guan
    • 1
  • Yong-Bo Tang
    • 1
  1. 1.Department of PharmacologyZhongshan School of Medicine, Sun Yat-Sen UniversityGuangzhouPeople’s Republic of China
  2. 2.Institute of Pharmacy and PharmacologyUniversity of South ChinaHengyangPeople’s Republic of China

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