Growth Inhibition and Apoptosis Induction of Human Umbilical Vein Endothelial Cells by Apogossypolone

  • Zhan, Yong-Hua (School of Life Sciences and Technology, Xidian University) ;
  • Huang, Xiao-Feng (Central Laboratory, School of Basic Medicine, Fourth Military Medical University) ;
  • Hu, Xing-Bin (Department of Blood Transfusion, Xijing Hospital, Fourth Military Medical University) ;
  • An, Qun-Xing (Department of Blood Transfusion, Xijing Hospital, Fourth Military Medical University) ;
  • Liu, Zhi-Xin (Department of Blood Transfusion, Xijing Hospital, Fourth Military Medical University) ;
  • Zhang, Xian-Qing (Department of Blood Transfusion, Xijing Hospital, Fourth Military Medical University)
  • Published : 2013.03.30


Aims and Background: Prostate cancer is one of the most common malignant tumors in the male reproductive system, which causes the second most cancer deaths of males, and control of angiogenesis in prostate lesions is of obvious importance. This study assessed the effect of apogossypolone (ApoG2) on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs). Subjects and Methods: HUVECs were treated with different concentrations of ApoG2. The survival rate of HUVECs were determined by MTT assay. Utrastructural changes of HUVECs were assessed with transmission electron microscopy. Apoptosis in HUVECs was analyzed by flow cytometry and cell migration by Boyden chamber assay. Matrigel assays were used to quantify the development of tube-like networks. Results: ApoG2 significantly inhibited HUVEC growth even at 24 h (P<0.05). The inhibitory effect of ApoG2 is more obvious as the concentration and the culture time increased (P<0.05). These results indicate that ApoG2 inhibits the proliferation of HUVECs in a time- and concentration-dependent manner with increase of the apoptosis rate. Besides, ApoG2 reduced the formation of total pseudotubule length and network branches of HUVECs. Conclusions: The results suggest that ApoG2 inhibits angiogenesis of HUVECs by growth inhibition and apoptosis induction.


  1. Abdollahi A, Lipson KE, Sckell A, et al (2003). Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects. Cancer Res, 63, 8890-8.
  2. Aragon-Ching JB, Madan RA, Dahut WL (2010). Angiogenesis inhibition in prostate cancer: current uses and future promises. J Oncol, 2010, 361836-42.
  3. Arnold AA, Aboukameel A, Chen J, et al (2008). Preclinical studies of Apogossypolone: a new nonpeptidic pan smallmolecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in Follicular Small Cleaved Cell Lymphoma model. Mol Cancer, 7, 20-9.
  4. Assadian S, El-Assaad W, Wang XQ, et al (2012). p53 inhibits angiogenesis by inducing the production of Arresten. Cancer Res, 72, 1270-9.
  5. Bagley RG, Rouleau C, Weber W, et al (2011). Tumor endothelial marker 7(TEM-7): a novel target for antiangiogenic therapy. Microvasc Res, 82, 253-62.
  6. Brawer MK, Deering RE, Brown M, Preston SD, Bigler SA (1994). Predictors of pathologic stage in prostatic carcinoma. The role of neovascularity. Cancer, 73, 678-87.<678::AID-CNCR2820730329>3.0.CO;2-6
  7. Carmeliet P, Ferreira V, Breier G, et al (1996). Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature, 380, 435-9.
  8. Ebos JM, Lee CR, Cruz-Munoz W, et al (2009). Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell, 15, 232-9.
  9. Ferrara N, Carver-Moore K, Chen H, et al (1996). Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature, 380, 439-42.
  10. Fidler IJ, Ellis LM (1994). The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell, 79, 185-8.
  11. Gyftopoulos K, Vourda K, Sakellaropoulos G, et al (2011). The angiogenic switch for vascular endothelial growth factor-A and cyclooxygenase-2 in prostate carcinoma: correlation with microvessel density, androgen receptor content and Gleason grade. Urol Int, 87, 464-9.
  12. Hanahan D (1997). Signaling vascular morphogenesis and maintenance. Science, 277, 48-50.
  13. Holash J, Wiegand SJ, Yancopoulos GD (1999). New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF. Oncogene, 18, 5356-62.
  14. Hood JD, Bednarski M, Frausto R, et al (2002). Tumor regression by targeted gene delivery to the neovasculature. Science, 296, 2404-7.
  15. Hu ZY, Zhu XF, Zhong ZD, et al (2008). ApoG2, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces apoptosis and suppresses tumor growth in nasopharyngeal carcinoma xenografts. Int J Cancer, 123, 2418-29.
  16. Konno H, Tanaka T, Matsuda I, et al (1995). Comparison of the inhibitory effect of the angiogenesis inhibitor, TNP-470, and mitomycin C on the growth and liver metastasis of human colon cancer. Int J Cancer, 61, 268-71.
  17. Lynch TP, Ferrer CM, Jackson SR, et al (2012). Critical role of O-GlcNAc transferase in prostate cancer invasion, angiogenesis and metastasis. J Biol Chem, 287, 11070-81.
  18. Mi JX, Wang GF, Wang HB, et al (2008). Synergistic antitumoral activity and induction of apoptosis by novel pan Bcl-2 proteins inhibitor apogossypolone with adriamycin in human hepatocellular carcinoma. Acta Pharmacol Sin, 29, 1467-77.
  19. Mucci LA, Powolny A, Giovannucci E, et al (2009). Prospective study of prostate tumor angiogenesis and cancer-specific mortality in the health professionals follow-up study. J Clin Oncol, 27, 5627-33.
  20. O'Reilly MS, Holmgren L, Shing Y, et al (1994). Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell, 79, 315-28.
  21. Pàez-Ribes M, Allen E, Hudock J, et al (2009). Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell, 15, 220-31
  22. Pande D, Negi R, Karki K, et al (2012). Simultaneous progression of oxidative stress, angiogenesis, and cell proliferation in prostatecarcinoma. Urol Oncol, [Epub ahead of print].
  23. Pinto A, Merino M, Zamora P, et al (2012). Targeting the endothelin axis in prostate carcinoma. Tumour Biol, 33, 421-6.
  24. Risau W (1997). Mechanisms of angiogenesis. Nature, 386, 671-4.
  25. Shelley MD, Hartley L, Fish RG, et al (1999). Stereo-specific cytotoxic effects of gossypol enantiomers and gossypolone in tumour cell lines. Cancer Lett, 135, 171-80.
  26. Sun J, Li ZM, Hu ZY, et al (2008). ApoG2 inhibits antiapoptotic Bcl-2 family proteins and induces mitochondria-dependent apoptosis in human lymphoma U937 cells. Anticancer Drugs, 19, 967-74.
  27. Weidner N, Carroll PR, Flax J, Blumenfeld W, Folkman J (1993). Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma. Am J Pathol, 143, 401-9.
  28. Weidner N, Semple JP, Welch WR, Folkman J (1991). Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. N Engl J Med, 324, 1-8.
  29. Zetter BR (1998). Angiogenesis and tumor metastasis. Annu Rev Med, 49, 407-24.
  30. Zhang XQ, Huang XF, Hu XB, et al (2010b). Apogossypolone, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces autophagy of PC-3 and LNCaP prostate cancer cells in vitro. Asian J Androl, 12, 697-708.
  31. Zhang XQ, Huang XF, Mu SJ, et al (2009). Inhibitory effect of a new gossypol derivative apogossypolone (ApoG2) on xenograft of human prostate cancer cell line PC-3. J Med Coll PLA (China), 24, 274-82.
  32. Zhang XQ, Huang XF, Mu SJ, et al (2010a). Inhibition of proliferation of prostate cancer cell line, PC-3, in vitro and in vivo using (-)-gossypol. Asian J Androl, 12, 390-9.

Cited by

  1. In vitro Study of the Antagonistic Effect of Low-dose Liquiritigenin on Gemcitabine-induced Capillary Leak Syndrome in Pancreatic Adenocarcinoma via Inhibiting ROS-Mediated Signalling Pathways vol.16, pp.10, 2015,
  2. Apogossypolone induces apoptosis and autophagy in nasopharyngeal carcinoma cells in an in vitro and in vivo study vol.14, pp.1, 2017,
  3. The anti-angiogenic potential of (±) gossypol in comparison to suramin pp.1573-0778, 2018,