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Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells

  • Authors:
    • Lu Zhao
    • Yue Zhao
    • Bettina Schwarz
    • Josef Mysliwietz
    • Roland Hartig
    • Peter Camaj
    • Qi Bao
    • Karl-Walter Jauch
    • Makus Guba
    • Joachim Walter Ellwart
    • Peter Jon Nelson
    • Christiane Josephine Bruns
  • View Affiliations / Copyright

    Affiliations: Department of Surgery, Otto-von-Guericke University, Magdeburg, Germany, Department of Surgery, Munich Medical Center, Campus Grosshadern, LMU, Munich, Germany, Institute of Molecular Immunology, Helmholtz Center for Environment and Health, Munich, Germany, Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany, Clinical Biochemistry Group, Medical Clinic and Policlinic IV, Munich Medical Center, Campus Innenstadt, LMU, Munich, Germany
    Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 99-110
    |
    Published online on: May 10, 2016
       https://doi.org/10.3892/ijo.2016.3512
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Abstract

Tumor side population (SP) cells display stem-like properties that can be modulated by treatment with the calcium channel blocker verapamil. Verapamil can enhance the cytotoxic effects of chemotherapeutic drugs and multidrug resistance by targeting the transport function of the P-glycoprotein (P-gp). This study focused on the therapeutic potential of verapamil on stem-like SP tumor cells, and further investigated its chemosensitizing effects using L3.6pl and AsPC-1 pancreatic carcinoma models. As compared to parental L3.6pl cells (0.9±0.22%), L3.6pl gemcitabine-resistant cells (L3.6plGres) showed a significantly higher percentage of SP cells (5.38±0.99%) as detected by Hoechst 33342/FACS assays. The L3.6plGres SP cells showed stable gemcitabine resistance, enhanced colony formation ability and increased tumorigenicity. Verapamil effectively inhibited L3.6plGres and AsPC-1 SP cell proliferation in vitro. A pro-apoptotic effect of verapamil was observed in L3.6pl cells, but not in L3.6plGres cells, which was linked to their differential expression of P-gp and equilibrative nucleoside transporter-1 (ENT-1). In an orthotopic pancreatic cancer mouse model, both low and high dose verapamil was shown to substantially reduce L3.6plGres-SP cell tumor growth and metastasis, enhance tumor apoptosis, and reduce microvascular density.
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Spandidos Publications style
Zhao L, Zhao Y, Schwarz B, Mysliwietz J, Hartig R, Camaj P, Bao Q, Jauch K, Guba M, Ellwart JW, Ellwart JW, et al: Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells. Int J Oncol 49: 99-110, 2016.
APA
Zhao, L., Zhao, Y., Schwarz, B., Mysliwietz, J., Hartig, R., Camaj, P. ... Bruns, C.J. (2016). Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells. International Journal of Oncology, 49, 99-110. https://doi.org/10.3892/ijo.2016.3512
MLA
Zhao, L., Zhao, Y., Schwarz, B., Mysliwietz, J., Hartig, R., Camaj, P., Bao, Q., Jauch, K., Guba, M., Ellwart, J. W., Nelson, P. J., Bruns, C. J."Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells". International Journal of Oncology 49.1 (2016): 99-110.
Chicago
Zhao, L., Zhao, Y., Schwarz, B., Mysliwietz, J., Hartig, R., Camaj, P., Bao, Q., Jauch, K., Guba, M., Ellwart, J. W., Nelson, P. J., Bruns, C. J."Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells". International Journal of Oncology 49, no. 1 (2016): 99-110. https://doi.org/10.3892/ijo.2016.3512
Copy and paste a formatted citation
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Spandidos Publications style
Zhao L, Zhao Y, Schwarz B, Mysliwietz J, Hartig R, Camaj P, Bao Q, Jauch K, Guba M, Ellwart JW, Ellwart JW, et al: Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells. Int J Oncol 49: 99-110, 2016.
APA
Zhao, L., Zhao, Y., Schwarz, B., Mysliwietz, J., Hartig, R., Camaj, P. ... Bruns, C.J. (2016). Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells. International Journal of Oncology, 49, 99-110. https://doi.org/10.3892/ijo.2016.3512
MLA
Zhao, L., Zhao, Y., Schwarz, B., Mysliwietz, J., Hartig, R., Camaj, P., Bao, Q., Jauch, K., Guba, M., Ellwart, J. W., Nelson, P. J., Bruns, C. J."Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells". International Journal of Oncology 49.1 (2016): 99-110.
Chicago
Zhao, L., Zhao, Y., Schwarz, B., Mysliwietz, J., Hartig, R., Camaj, P., Bao, Q., Jauch, K., Guba, M., Ellwart, J. W., Nelson, P. J., Bruns, C. J."Verapamil inhibits tumor progression of chemotherapy-resistant pancreatic cancer side population cells". International Journal of Oncology 49, no. 1 (2016): 99-110. https://doi.org/10.3892/ijo.2016.3512
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