Skip to main content

Advertisement

SpringerLink
Log in

Lidamycin up-regulates the expression of thymidine phosphorylase and enhances the effects of capecitabine on the growth and pulmonary metastases of murine breast carcinoma

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Capecitabine (CAP), a prodrug, needs to be converted to 5-fluorouracil by several key enzymes, including thymidine phosphorylase (TP). To improve the therapeutic index, potentiation of antitumor activity of CAP is required. In this study, we explored whether lidamycin (LDM), an enediyne anticancer antibiotic, can induce synergistic antitumor effects in combination with CAP in murine breast cancer in vitro and in vivo.

Methods

Using MTT, cell migration and invasion, siRNA knockdown, and Western blot assays, the in vitro synergistic effects of LDM plus CAP on 4T1LUC cells were evaluated, and the mechanism of this synergy was explored. For in vivo model of orthotopic implantation model of 4T1LUC cells, optical molecular imaging system was utilized to evaluate the growth of primary tumor and metastasis. To further understand the mechanism of action of the LDM/CAP combination, immunohistochemistry analysis was carried out to detect thymidine phosphorylase induction and ERK signaling.

Results

As determined by MTT and transwell assay, LDM enhanced the inhibitory effects of CAP on cancer cell proliferation, migration, and invasion. Western blot showed that this synergistic effect was attributed to the up-regulated expression of TP induced by LDM. Knocking down TP impaired the synergistic anti-proliferative effect of LDM and CAP. Furthermore, our data suggested that LDM-induced up-regulation of TP both in vitro and in vivo is associated with ERK activation, because the inhibition of ERK activity by ERK inhibitor U0126 abrogated LDM-induced TP up-regulation. In animal models, LDM plus CAP potently inhibited primary tumor growth as well as lung metastasis compared with control or single-agent-treated group.

Conclusions

LDM can potentiate the antitumor effects of CAP on breast cancer line. The synergistic effects suggest that the combination of LDM and CAP is an innovative antitumor strategy for breast cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA: A Cancer Journal for Clinicians 63(1):11–30

    Article  Google Scholar 

  2. Boyle P (2005) Breast cancer control: signs of progress, but more work required. Breast 14(6):429–438

    Article  PubMed  Google Scholar 

  3. Demicheli R, Valagussa P, Bonadonna G (2001) Does surgery modify growth kinetics of breast cancer micrometastases? Br J Cancer 85(4):490–492

    Article  PubMed  CAS  Google Scholar 

  4. Hansen E, Wolff N, Knuechel R, Ruschoff J, Hofstaedter F, Taeger K (1995) Tumor cells in blood shed from the surgical field. Arch Surg 130(4):387–393

    Article  PubMed  CAS  Google Scholar 

  5. Hu JL, Xue YC, Xie MY, Zhang R, Otani T, Minami Y, Yamada Y, Marunaka T (1988) A new macromolecular antitumor antibiotic, C-1027. I. Discovery, taxonomy of producing organism, fermentation and biological activity. J Antibiot 41(11):1575–1579 Tokyo

    Article  PubMed  CAS  Google Scholar 

  6. Shao RG, Zhen YS (2008) Enediyne anticancer antibiotic lidamycin: chemistry, biology and pharmacology. Anticancer Agents Med Chem 8(2):123–131

    Article  PubMed  CAS  Google Scholar 

  7. Shao RG (2008) Pharmacology and therapeutic applications of enediyne antitumor antibiotics. Curr Mol Pharmacol 1(1):50–60

    PubMed  CAS  Google Scholar 

  8. Shao RG, Zhen YS (1995) Relationship between the molecular composition of C1027, a new macromolecular antibiotic with enediyne chromophore, and its antitumor activity. Yao Xue Xue Bao 30(5):336–342

    PubMed  CAS  Google Scholar 

  9. Dziegielewski J, Beerman TA (2002) Cellular responses to the DNA strand-scission enediyne C-1027 can be independent of ATM, ATR, and DNA-PK kinases. J Biol Chem 277(23):20549–20554

    Article  PubMed  CAS  Google Scholar 

  10. Beerman TA, Gawron LS, Shin S, Shen B, McHugh MM (2009) C-1027, a radiomimetic enediyne anticancer drug, preferentially targets hypoxic cells. Cancer Res 69(2):593–598

    Article  PubMed  CAS  Google Scholar 

  11. Chen L, Jiang J, Cheng C, Yang A, He Q, Li D, Wang Z (2007) P53 dependent and independent apoptosis induced by lidamycin in human colorectal cancer cells. Cancer Biol Ther 6(6):965–973

    Article  PubMed  CAS  Google Scholar 

  12. Liu H, Li L, Li XQ, Liu XJ, Zhen YS (2009) Enediyne lidamycin enhances the effect of epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib, in epidermoid carcinoma A431 cells and lung carcinoma H460 cells. Anticancer Drugs 20(1):41–49

    Article  PubMed  CAS  Google Scholar 

  13. Ding LL, Liu M, Zhang SH, Zhao XZ, Wu N, Chen L, Wang GJ, Lin XK (2010) Lidamycin inhibits angiogenesis of zebrafish embryo via down-regulation of VEGF. Yao Xue Xue Bao 45(4):456–461

    PubMed  CAS  Google Scholar 

  14. Esteva FJ, Valero V, Pusztai L, Boehnke-Michaud L, Buzdar AU, Hortobagyi GN (2001) Chemotherapy of metastatic breast cancer: what to expect in 2001 and beyond. Oncologist 6(2):133–146

    Article  PubMed  CAS  Google Scholar 

  15. Bollag W, Hartmann HR (1980) Tumor inhibitory effects of a new fluorouracil derivative: 5′-deoxy-5-fluorouridine. Eur J Cancer 16(4):427–432

    Article  PubMed  CAS  Google Scholar 

  16. Walko CM, Lindley C (2005) Capecitabine: a review. Clin Ther 27(1):23–44

    Article  PubMed  CAS  Google Scholar 

  17. Zimmerman M (1964) Deoxyribosyl Transfer. Ii. Nucleoside:pyrimidine deoxyribosyltransferase activity of three partially purified thymidine phosphorylases. J Biol Chem 239:2622–2627

    PubMed  CAS  Google Scholar 

  18. Sawada N, Ishikawa T, Sekiguchi F, Tanaka Y, Ishitsuka H (1999) X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts. Clin Cancer Res 5(10):2948–2953

    PubMed  CAS  Google Scholar 

  19. Morita T, Matsuzaki A, Tokue A (2001) Enhancement of sensitivity to capecitabine in human renal carcinoma cells transfected with thymidine phosphorylase cDNA. Int J Cancer 92(3):451–456

    Article  PubMed  CAS  Google Scholar 

  20. Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H (1998) Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 4(4):1013–1019

    PubMed  CAS  Google Scholar 

  21. Ciccolini J, Fina F, Bezulier K, Giacometti S, Roussel M, Evrard A, Cuq P, Romain S, Martin PM, Aubert C (2002) Transmission of apoptosis in human colorectal tumor cells exposed to capecitabine, Xeloda, is mediated via Fas. Mol Cancer Ther 1:923–927

    PubMed  CAS  Google Scholar 

  22. Chefrour M, Fischel JL, Formento P, Giacometti S, Ferri-Dessens RM, Marouani H, Francoual M, Renee N, Mercier C, Milano G, Ciccolini J (2010) Erlotinib in combination with capecitabine (5′dFUR) in resistant pancreatic cancer cell lines. J Chemother 22:129–133

    PubMed  CAS  Google Scholar 

  23. Chefrour M, Milano G, Formento P, Giacometti S, Denden A, Renée N, Iliadis A, Fischel J-L, Ciccolini J (2012) Positive interaction between lapatinib and capecitabine in human breast cancer models: study of molecular determinants. Fundam Clin Pharmacol 26:530–537

    Article  PubMed  CAS  Google Scholar 

  24. Fujimoto-Ouchi K, Tanaka Y, Tominaga T (2001) Schedule dependency of antitumor activity in combination therapy with capecitabine/5′-deoxy-5-fluorouridine and docetaxel in breast cancer models. Clin Cancer Res 7(4):1079–1086

    PubMed  CAS  Google Scholar 

  25. Gong JH, Liu XJ, Li Y, Zhen YS (2012) Pingyangmycin downregulates the expression of EGFR and enhances the effects of cetuximab on esophageal cancer cells and the xenograft in athymic mice. Cancer Chemoth Pharm 69:1323–1332

    Article  CAS  Google Scholar 

  26. Ren K, Jin H, Bian C, He H, Liu X, Zhang S, Wang Y, Shao RG (2008) MR-1 modulates proliferation and migration of human hepatoma HepG2 cells through myosin light chains-2 (MLC2)/focal adhesion kinase (FAK)/Akt signaling pathway. J Biol Chem 283(51):35598–35605

    Article  PubMed  CAS  Google Scholar 

  27. Bibby MC (2004) Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages. Eur J Cancer 40(6):852–857

    Article  PubMed  CAS  Google Scholar 

  28. Eccles SA, Box G, Court W, Sandle J, Dean CJ (1994) Preclinical models for the evaluation of targeted therapies of metastatic disease. Cell Biophys 24–25:279–291

    PubMed  Google Scholar 

  29. Hoffman RM (1999) Orthotopic metastatic mouse models for anticancer drug discovery and evaluation: a bridge to the clinic. Invest New Drugs 17(4):343–359

    Article  PubMed  CAS  Google Scholar 

  30. Vernon AE, Bakewell SJ, Chodosh LA (2007) Deciphering the molecular basis of breast cancer metastasis with mouse models. Rev Endocr Metab Disord 8(3):199–213

    Article  PubMed  CAS  Google Scholar 

  31. Eckhardt BL, Parker BS, van Laar RK, Restall CM, Natoli AL, Tavaria MD, Stanley KL, Sloan EK, Moseley JM, Anderson RL (2005) Genomic analysis of a spontaneous model of breast cancer metastasis to bone reveals a role for the extracellular matrix. Mol Cancer Res 3(1):1–13

    PubMed  CAS  Google Scholar 

  32. Yoneda T, Michigami T, Yi B, Williams PJ, Niewolna M, Hiraga T (2000) Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma. Cancer 88(12 Suppl):2979–2988

    Article  PubMed  CAS  Google Scholar 

  33. Aslakson CJ, Miller FR (1992) Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 52(6):1399–1405

    PubMed  CAS  Google Scholar 

  34. Lelekakis M, Moseley JM, Martin TJ, Hards D, Williams E, Ho P, Lowen D, Javni J, Miller FR, Slavin J, Anderson RL (1999) A novel orthotopic model of breast cancer metastasis to bone. Clin Exp Metastasis 17(2):163–170

    Article  PubMed  CAS  Google Scholar 

  35. Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, Osterwalder B, Burger HU, Brown CS, Griffin T (1999) Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17(2):485–493

    PubMed  CAS  Google Scholar 

  36. Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34(8):1274–1281

    Article  PubMed  CAS  Google Scholar 

  37. Schuller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, Utoh M, Mori K, Weidekamm E, Reigner B (2000) Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45(4):291–297

    Article  PubMed  CAS  Google Scholar 

  38. Bijnsdorp IV, de Bruin M, Laan AC, Fukushima M, Peters GJ (2008) The role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in tumor behavior. Nucleosides, Nucleotides Nucleic Acids 27(6):681–691

    Article  PubMed  CAS  Google Scholar 

  39. Ko JC, Tsai MS, Chiu YF, Weng SH, Kuo YH, Lin YW (2011) Up-regulation of extracellular signal-regulated kinase 1/2-dependent thymidylate synthase and thymidine phosphorylase contributes to cisplatin resistance in human non-small-cell lung cancer cells. J Pharmacol Exp Ther 338(1):184–194

    Article  PubMed  CAS  Google Scholar 

  40. Liekens S, Bronckaers A, Perez–Perez MJ, Balzarini J (2007) Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy. Biochem Pharmacol 74(11):1555–1567

    Article  PubMed  CAS  Google Scholar 

  41. Chen J, Ouyang ZG, Zhang SH, Zhen YS (2007) Down-regulation of the nuclear factor-kappaB by lidamycin in association with inducing apoptosis in human pancreatic cancer cells and inhibiting xenograft growth. Oncol Rep 17(6):1445–1451

    PubMed  CAS  Google Scholar 

  42. Huang YH, Shang BY, Zhen YS (2005) Antitumor efficacy of lidamycin on hepatoma and active moiety of its molecule. World J Gastroenterol 11(26):3980–3984

    PubMed  CAS  Google Scholar 

  43. Eda H, Fujimoto K, Watanabe S, Ura M, Hino A, Tanaka Y, Wada K, Ishitsuka H (1993) Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5′-deoxy-5-fluorouridine. Cancer Chemother Pharmacol 32(5):333–338

    Article  PubMed  CAS  Google Scholar 

  44. Eda H, Fujimoto K, Watanabe S, Ishikawa T, Ohiwa T, Tatsuno K, Tanaka Y, Ishitsuka H (1993) Cytokines induce uridine phosphorylase in mouse colon 26 carcinoma cells and make the cells more susceptible to 5′-deoxy-5-fluorouridine. Jpn J Cancer Res 84(3):341–347

    Article  PubMed  CAS  Google Scholar 

  45. Tevaearai HT, Laurent PL, Suardet L, Eliason JF, Givel JC, Odartchenko N (1992) Interactions of interferon-alpha 2a with 5′-deoxy-5-fluorouridine in colorectal cancer cells in vitro. Eur J Cancer 28(2–3):368–372

    Article  PubMed  CAS  Google Scholar 

  46. Zhu GH, Lenzi M, Schwartz EL (2002) The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells. Oncogene 21(55):8477–8485

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by Grants from National Basic Research Program of China (No. 2009CB521807) and National Mega-project for Innovative Drugs (No. 2012ZX09301002-001). Open Project Program of State Key Laboratory of Oncology in South China (No. HN2012-03).

Conflict of interest

The authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China

    Sheng-hua Zhang, Hao Zhang, Hong-wei He, Liang Li & Rong-guang Shao

  2. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, 510060, China

    Sheng-hua Zhang

  3. College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing, 163319, Heilongjiang, China

    Xing-qi Li

  4. Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China

    Yi-ping Zhang

Authors
  1. Sheng-hua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong-wei He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xing-qi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi-ping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rong-guang Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yi-ping Zhang or Rong-guang Shao.

Additional information

Sheng-hua Zhang and Hao Zhang have contributed equally, as co-first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, Sh., Zhang, H., He, Hw. et al. Lidamycin up-regulates the expression of thymidine phosphorylase and enhances the effects of capecitabine on the growth and pulmonary metastases of murine breast carcinoma. Cancer Chemother Pharmacol 72, 777–788 (2013). https://doi.org/10.1007/s00280-013-2253-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-013-2253-3

Keywords

Search

Navigation