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Bevacizumab enhances chemosensitivity of hepatocellular carcinoma to adriamycin related to inhibition of survivin expression

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Abstract

Purpose

In recent years, anti-angiogenesis drugs have shown promising clinical effects against many tumors, particularly in combination with chemotherapy. Although the combination has become a standard of care for many tumors, the mechanisms of the chemosensitizing activity of anti-angiogenic drugs are not fully understood. Here, we sought to determine if anti-angiogenesis drug bevacizumab could enhance the chemosensitivity of HCC by inhibition of survivin.

Methods

After treatment of human umbilical vein endothelial cells (HUVECs) and hepatocellular carcinoma (HCC) cell line PLC/PRF/5 (PLC) with bevacizumab or/and adriamycin, the direct effects were examined by survival assays, and the expression of Akt, Phospho-Akt and survivin were evaluated by western blot. Tumor growth was observed in a human HCC xenograft nude mouse model treated with different drugs, and the expression of PCNA, CD31 and survivin in tumor tissues were evaluated by means of immunohistochemistry.

Results

Bevacizumab enhanced the chemosensitivity of HCC by inhibiting the VEGF-PI3 K/Akt-survivin signaling cascade in endothelial cells. The combination of bevacizumab with adriamycin therapy resulted in better outcomes compared with monotherapy in hepatocellular carcinoma xenografts; bevacizumab significantly inhibited tumor angiogenesis and growth. In addition, bevacizumab reduced survivin expression in tumor tissues, including tumor vascular endothelial cells in vivo, although it did not inhibit survivin expression in tumor cells in vitro.

Conclusion

These results implicate the bevacizumab-increased efficacy of adriamycin via an inhibition of survivin expression in malignant cells as well as tumor vasculature cells, which provides other insights into the mechanism of enhanced efficacy by combination of VEGF blocker and chemotherapeutic agents.

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References

  • Altieri DC (2008) Survivin, cancer networks and pathway-directed drug discovery. Nat Rev Cancer 8:61–70

    Article  CAS  PubMed  Google Scholar 

  • Altznauer F, Martinelli S, Yousefi S, Thurig C, Schmid I, Conway EM, Schoni MH, Vogt P, Mueller C, Fey MF, Zangemeister-Wittke U, Simon HU (2004) Inflammation-associated cell cycle-independent block of apoptosis by survivin in terminally differentiated neutrophils. J Exp Med 199:1343–1354

    Article  CAS  PubMed  Google Scholar 

  • Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3:401–410

    Article  CAS  PubMed  Google Scholar 

  • Blanc-Brude OP, Mesri M, Wall NR, Plescia J, Dohi T, Altieri DC (2003) Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis. Clin Cancer Res 9:2683–2692

    CAS  PubMed  Google Scholar 

  • Bruix J, Llovet JM (2002) Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 35:519–524

    Article  PubMed  Google Scholar 

  • Caldas H, Fangusaro JR, Boue DR, Holloway MP, Altura RA (2007) Dissecting the role of endothelial SURVIVIN DeltaEx3 in angiogenesis. Blood 109:1479–1489

    Article  CAS  PubMed  Google Scholar 

  • Cosgrave N, Hill AD, Young LS (2006) Growth factor-dependent regulation of survivin by c-myc in human breast cancer. J Mol Endocrinol 37:377–390

    Article  CAS  PubMed  Google Scholar 

  • Ferrara N (2005) The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS 94:209–231

    PubMed  Google Scholar 

  • Fields AC, Cotsonis G, Sexton D, Santoianni R, Cohen C (2004) Survivin expression in hepatocellular carcinoma: correlation with proliferation, prognostic parameters, and outcome. Mod Pathol 17:1378–1385

    Article  CAS  PubMed  Google Scholar 

  • Finn RS, Zhu AX (2009) Targeting angiogenesis in hepatocellular carcinoma: focus on VEGF and bevacizumab. Expert Rev Anticancer Ther 9:503–509

    Article  CAS  PubMed  Google Scholar 

  • Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67:3560–3564

    Article  CAS  PubMed  Google Scholar 

  • Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  CAS  PubMed  Google Scholar 

  • Ito T, Shiraki K, Sugimoto K, Yamanaka T, Fujikawa K, Ito M, Takase K, Moriyama M, Kawano H, Hayashida M, Nakano T, Suzuki A (2000) Survivin promotes cell proliferation in human hepatocellular carcinoma. Hepatology 31:1080–1085

    Article  CAS  PubMed  Google Scholar 

  • Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62

    Article  CAS  PubMed  Google Scholar 

  • Kawasaki H, Toyoda M, Shinohara H, Okuda J, Watanabe I, Yamamoto T, Tanaka K, Tenjo T, Tanigawa N (2001) Expression of survivin correlates with apoptosis, proliferation, and angiogenesis during human colorectal tumorigenesis. Cancer 91:2026–2032

    Article  CAS  PubMed  Google Scholar 

  • Kerbel RS (2006) Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 312:1171–1175

    Article  CAS  PubMed  Google Scholar 

  • Le Gouill S, Podar K, Amiot M, Hideshima T, Chauhan D, Ishitsuka K, Kumar S, Raje N, Richardson PG, Harousseau JL, Anderson KC (2004) VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis. Blood 104:2886–2892

    Article  CAS  PubMed  Google Scholar 

  • Li F, Ling X (2006) Survivin study: an update of “what is the next wave”? J Cell Physiol 208:476–486

    Article  CAS  PubMed  Google Scholar 

  • Marusawa H, Matsuzawa S, Welsh K, Zou H, Armstrong R, Tamm I, Reed JC (2003) HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J 22:2729–2740

    Article  CAS  PubMed  Google Scholar 

  • Mesri M, Morales-Ruiz M, Ackermann EJ, Bennett CF, Pober JS, Sessa WC, Altieri DC (2001) Suppression of vascular endothelial growth factor-mediated endothelial cell protection by survivin targeting. Am J Pathol 158:1757–1765

    Article  CAS  PubMed  Google Scholar 

  • Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676

    Article  CAS  PubMed  Google Scholar 

  • Moriai R, Tsuji N, Moriai M, Kobayashi D, Watanabe N (2008) Survivin plays as a resistant factor against tamoxifen-induced apoptosis in human breast cancer cells. Breast Cancer Res Treat 117:261–271

    Article  PubMed  Google Scholar 

  • Nakagawa Y, Abe S, Kurata M, Hasegawa M, Yamamoto K, Inoue M, Takemura T, Suzuki K, Kitagawa M (2006) IAP family protein expression correlates with poor outcome of multiple myeloma patients in association with chemotherapy-induced overexpression of multidrug resistance genes. Am J Hematol 81:824–831

    Article  CAS  PubMed  Google Scholar 

  • O’Connor DS, Schechner JS, Adida C, Mesri M, Rothermel AL, Li F, Nath AK, Pober JS, Altieri DC (2000) Control of apoptosis during angiogenesis by survivin expression in endothelial cells. Am J Pathol 156:393–398

    Article  PubMed  Google Scholar 

  • Podar K, Tonon G, Sattler M, Tai YT, Legouill S, Yasui H, Ishitsuka K, Kumar S, Kumar R, Pandite LN, Hideshima T, Chauhan D, Anderson KC (2006) The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. Proc Natl Acad Sci USA 103:19478–19483

    Article  CAS  PubMed  Google Scholar 

  • Riedel F, Gotte K, Goessler U, Sadick H, Hormann K (2004) Targeting chemotherapy-induced VEGF up-regulation by VEGF antisense oligonucleotides in HNSCC cell lines. Anticancer Res 24:2179–2183

    CAS  PubMed  Google Scholar 

  • Sakurai T, Maeda S, Chang L, Karin M (2006) Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci U S A 103:10544–10551

    Article  CAS  PubMed  Google Scholar 

  • Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D’Amato RJ, Kerbel RS (2005) Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7:101–111

    CAS  PubMed  Google Scholar 

  • Singh RP, Dhanalakshmi S, Agarwal C, Agarwal R (2005) Silibinin strongly inhibits growth and survival of human endothelial cells via cell cycle arrest and downregulation of survivin, Akt and NF-kappaB: implications for angioprevention and antiangiogenic therapy. Oncogene 24:1188–1202

    Article  CAS  PubMed  Google Scholar 

  • Tran J, Master Z, Yu JL, Rak J, Dumont DJ, Kerbel RS (2002) A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci U S A 99:4349–4354

    Article  CAS  PubMed  Google Scholar 

  • Tu SP, Cui JT, Liston P, Xiao HJ, Xu R, Lin MC, Zhu YB, Zou B, Ng SS, Jiang SH, Xia HH, Wong WM, Chan AO, Yuen MF, Lam SK, Kung HF, Wong BC (2005) Gene therapy for colon cancer by adeno-associated viral vector-mediated transfer of survivin Cys84Ala mutant. Gastroenterology 128:361–375

    Article  CAS  PubMed  Google Scholar 

  • Virrey JJ, Guan S, Li W, Schonthal AH, Chen TC, Hofman FM (2008) Increased survivin expression confers chemoresistance to tumor-associated endothelial cells. Am J Pathol 173:575–585

    Article  CAS  PubMed  Google Scholar 

  • Xiang R, Mizutani N, Luo Y, Chiodoni C, Zhou H, Mizutani M, Ba Y, Becker JC, Reisfeld RA (2005) A DNA vaccine targeting survivin combines apoptosis with suppression of angiogenesis in lung tumor eradication. Cancer Res 65:553–561

    CAS  PubMed  Google Scholar 

  • Xin H, Zhang C, Herrmann A, Du Y, Figlin R, Yu H (2009) Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res 69:2506–2513

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto H, Ngan CY, Monden M (2008) Cancer cells survive with survivin. Cancer Sci 99:1709–1714

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Cao Z, Li F, Post DE, Van Meir EG, Zhong H, Wood WC (2004) Tumor-specific gene expression using the survivin promoter is further increased by hypoxia. Gene Ther 11:1215–1223

    Article  CAS  PubMed  Google Scholar 

  • Zaffaroni N, Daidone MG (2002) Survivin expression and resistance to anticancer treatments: perspectives for new therapeutic interventions. Drug Resist Updat 5:65–72

    Article  CAS  PubMed  Google Scholar 

  • Zaffaroni N, Pennati M, Daidone MG (2005) Survivin as a target for new anticancer interventions. J Cell Mol Med 9:360–372

    Article  CAS  PubMed  Google Scholar 

  • Zhu AX, Blaszkowsky LS, Ryan DP, Clark JW, Muzikansky A, Horgan K, Sheehan S, Hale KE, Enzinger PC, Bhargava P, Stuart K (2006) Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 24:1898–1903

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by National Natural Science Foundation of China (30731160005, 30872504), China National “211” Project for Higher Education, and National Key Science and Technology Specific Project (2008ZX10002-019, 021).

Conflict of interest statement

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Authors and Affiliations

  1. Liver Cancer Institute and Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, People’s Republic of China

    Yu-Quan Xiong, Hui-Chuan Sun, Xiao-Dong Zhu, Wei Zhang, Peng-Yuan Zhuang, Ju-Bo Zhang, Hua-Xiang Xu, Ling-Qun Kong, Wei-Zhong Wu, Lun-Xiu Qin & Zhao-You Tang

  2. Education Ministry Key Laboratory of Carcinogenesis and Cancer Invasion, Shanghai, 200032, People’s Republic of China

    Yu-Quan Xiong, Hui-Chuan Sun, Xiao-Dong Zhu, Wei Zhang, Peng-Yuan Zhuang, Ju-Bo Zhang, Hua-Xiang Xu, Ling-Qun Kong, Wei-Zhong Wu, Lun-Xiu Qin & Zhao-You Tang

  3. Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, People’s Republic of China

    Yu-Quan Xiong, Lun-Xiu Qin & Zhao-You Tang

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  1. Yu-Quan Xiong
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  2. Hui-Chuan Sun
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  4. Wei Zhang
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  7. Hua-Xiang Xu
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  8. Ling-Qun Kong
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  9. Wei-Zhong Wu
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  10. Lun-Xiu Qin
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  11. Zhao-You Tang
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Corresponding author

Correspondence to Zhao-You Tang.

Additional information

Y.-Q. Xiong and H.-C. Sun contributed equally to this work.

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Xiong, YQ., Sun, HC., Zhu, XD. et al. Bevacizumab enhances chemosensitivity of hepatocellular carcinoma to adriamycin related to inhibition of survivin expression. J Cancer Res Clin Oncol 137, 505–512 (2011). https://doi.org/10.1007/s00432-010-0914-8

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  • DOI: https://doi.org/10.1007/s00432-010-0914-8

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