Abstract
The main goal of this study was to investigate whether lidamycin (LDM) could enhance the efficacy of paclitaxel (TAX) against breast cancer. In the MTT assay, LDM showed much more potent cytotoxicity than paclitaxel, and there was a synergy on the 4T1/luc breast cancer cells treated with a combination of paclitaxel and LDM. Western blot analysis showed that paclitaxel and LDM synergistically downregulated MMP9, MMP2, VEGF, and upregulated the cleaved PARP proteins. By wound closure cell migration assay, paclitaxel combined LDM obviously inhibited the migration of 4T1/luc cells. At therapeutic dosage level, LDM, paclitaxel, and the combination suppressed the pulmonary metastases by 70.2%, 53.8%, and 88.7%, respectively, and the CDI value was 0.82, indicating synergism. The results show that LDM enhances the antitumor effect of paclitaxel on 4T1/luc breast cancer, in particular, the antimetastatic effects on pulmonary metastasis.
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Jiang H C, Tao W Y, Zhang M, et al. Low-Dose metronomic paclitaxel chemotherapy suppresses breast tumors and metastases in mice. Cancer Investigation, 2010, 28: 74–84
Demichell R, Valagussa P, Bonadonna G. Does surgery modify growth kinetics of breast cancer micrometastases. Br J Cancer, 2001, 85: 490–492
Hansen E, Wolff N, Knuechel R, et al. Tumor cells in bloodshed from the surgical field. Arch Surg, 1995, 130: 387–393
Arbuck S G, Dorr A, Friedman M A. Paclitaxel (Taxol) in breast cancer. Hematol Oncol Clin North Am, 1994, 8: 121–140
Horwitz S B, Cohen D, Rao S, et al. Paclitaxel: Mechanisms of action and resistance. J Natl Cancer Inst, 1993, 15: 55–61
Davidson N G. Single-agent paclitaxel as first-line treatment of metastatic breast cancer: The British experience. Semin Oncol, 1996, 23: 6–10
Holmes F A, Valero V, Walters R S, et al. The M.D. Anderson Cancer Center experience with taxol in metastatic breast cancer. J Natl Cancer Inst Monogr, 1993, 15: 161–169
Seidman A D, Reichman B S, Crown J P, et al. Paclitaxel as second and subsequent therapy for metastatic breast cancer: Activity independent of prior anthracycline response. J Clin Oncol, 1995, 13: 1152–1159
Fountzilas G, Athanassiades A, Giannakakia T, et al. A phase II study of paclitaxel in advanced breast cancer resistant to anthracyclines. Eur J Cancer, 1996, 32: 47–51
Hu J L, Xue Y C, Xie M Y, et al. A new macromolecular antitumor antibiotic, C-1027. I. Discovery, taxonomy of producing organism, fermentation and biological activity. Antibiotics, 1988, 41: 1575–1579
Shao R G, Zhen Y S. Enediyne anticancer antibiotic lidamycin: Chemistry, biology and pharmacology. Anticancer Agents Med Chem, 2008, 8: 121–131
Shao R G, Zhen Y S. Relationship between the molecular composition of C1027, a new macromolecular antibiotic with enediyne chromophore, and its antitumor activity. Acta Pharmcol Sin, 1995, 30: 336–342
Shao R G. Pharmacology and therapeutic applications of enediyne antitumor antibiotics. Curr Mol Pharmacol, 2008, 1: 50–60
Beerman T A, Gawron L S, Shin S, et al. C-1027, a radiomimetic enediyne anticancer drug, preferentially targets hypoxic cells. Cancer Res, 2009, 69: 593–598
Chen L, Jiang J, Cheng C, et al. P53 dependent and independent apoptosis induced by lidamycin in human colorectal cancer cells. Cancer Biol Therapy, 2007, 6: 965–973
Shi Y K, Wu S Y, Huang Y H, et al. Chemosensitivity of mdr1 gene overexpressed multidrug resistant cancer cells to lidamycin (in Chinese). Yao Xue Xue Bao, 2006, 41: 1146–1151
Liu H, Li L, Li X Q, et al. Enediyne lidamycin enhances the effect of epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib, in epidermoid carcinoma A431 cells and lung carcinoma H460 cells. Anti Cancer Drugs, 2009, 20: 41–49
Chen J, Wu S Y, Ouyang Z G, et al. Synergy of gemcitabine and lidamycin associated with NF-kappaB downregulation in pancreatic carcinoma cells. Acta Pharmacol Sin, 2008, 29: 614–619
Pulaski B A, Clements V K, Pipeling M R, et al. Immunotherapy with vaccines combining MHC class II/CD80+ tumor cells with interleukin-12 reduces established metastatic disease and stimulates immune effectors and monokine induced by interferon gamma. Cancer Immunol, 2000, 49: 34–45
Michigami T, Hiraga T, Williams P J, et al. The effect of the bisphosphonate ibandronate on breast cancer metastasis to visceral organs. Breast Cancer Res Treat, 2002, 75: 249–258
Hiraga T, Ueda A, Tamura D, et al. Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer. Int J Cancer, 2003, 106: 973–979
Yang J, Mani S A, Donaher J L. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell, 2004, 117: 927–939
Talia S F, Jeffrey D M, Mark E B, et al. The economic burden of metastatic breast cancer: A systematic review of literature from developed countries. Cancer Treatment Rev, 2011, 37: 405–415
Aslakson C J, Miller F R. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res, 1992, 52: 1399–1405
Lelekakis M, Moseley J M, Martin T J, et al. A novel orthotopic model of breast cancer metastasis to bone. Clin Exp Metastasis, 1999, 17: 163–170
Park S J, Kim R J, Nam J S. Inhibitor of DNA-binding 4 contributes to the maintenance and expansion of cancer stem cells in 4T1 mouse mammary cancer cell line. Lab Anim Res, 2011, 27: 333–338
Bao L, Haque A, Jackson K, et al. Increased expression of P-glycoprotein is associated with doxorubicin chemoresistance in the metastatic 4T1 breast cancer model. Am J Pathol, 2011, 178: 838–852
Jiang P D, Zhao Y L, Deng X Q, et al. Antitumor and antimetastatic activities of chloroquine diphosphate in a murine model of breast cancer. Biomed Pharmacother, 2010, 64: 609–614
Li J, Dong X, Xu Z, et al. Endostatin gene therapy enhances the efficacy of paclitaxel to suppress breast cancers and metastases in mice. J Biomed Sci, 2008, 15: 99–109
Zhen H Y, Xue Y, Zhen Y S. Inhibition of angiogenesis by antitumor antibiotic C-1027 and its effect on tumor metastasis. Natl Med J Chin, 1997, 77: 657–660
Huang Y H, Shang B Y, Zhen Y S. Antitumor efficacy of lidamycin on hepatoma and active moiety of its molecule. World J Gastroenterl, 2005, 11: 3980–3984
Chen J, Ouyang Z G, Zhang S H, et al. Down-regulation of the nuclear factor-?B by lidamycin in association with inducing apoptosis in human pancreatic cancer cells and inhibiting xenograft growth. Oncol Rep, 2007, 17: 1445–1451
Zhen Y Z, Lin Y J, Shang B Y, et al. Enediyne lidamycin induces apoptosis in human multiple myeloma cells through activation of p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase. Hematology, 2009, 90: 44–51
Guo X F, Zhu X F, Shang Y, et al. A bispecific enediyne-energized fusion protein containing ligand-based and antibody-based oligopeptides against epidermal growth factor receptor and human epidermal growth factor receptor2 shows potent antitumor activity. Clini Cancer Res, 2010, 16: 2085–2094
Li L, Huang Y H, Li Y, et al. Antitumor activity of anti-type IV collagenase monoclonal antibody and its lidamycin conjugate against colon carcinoma. World J Gastroenterol, 2005, 11: 4478–4483
Kennedy D R, Beerman T A. The radio mimetic enediyne C-1027 induces unusual DNA damage responses to double-strand breaks. Biochemistry 2006, 45: 3747–3754
He Q Y, Liang Y Y, Wang D S, et al. Characteristics of mitotic cell death induced by enediyne antibiotic lidamycin in human epithelial tumor cells. Int J Oncol, 2002, 20: 261–266
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Hu, L., Zhang, S., Shao, R. et al. Lidamycin inhibits tumor growth and pulmonary metastasis in murine breast carcinoma and shows synergy with paclitaxel. Chin. Sci. Bull. 58, 2805–2811 (2013). https://doi.org/10.1007/s11434-013-5732-3
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DOI: https://doi.org/10.1007/s11434-013-5732-3