Share This Article:

Exploiting MCF-7 Cells’ Calcium Dependence with Interlaced Therapy

Abstract Full-Text HTML Download Download as PDF (Size:3468KB) PP. 32-40
DOI: 10.4236/jct.2013.47A006    3,554 Downloads   5,088 Views   Citations


The purpose of this study is to demonstrate MCF-7 cells’ dependence on calcium for growth and to exploit that dependence to improve chemotherapy efficacy. Fura-2 fluorescence imaging shows that MCF-7 cells maintain a higher basal intracellular calcium concentration than non-tumorigenic MCF-10A cells. Blocking T-type calcium channels with mibefradil reduced MCF-7 intracellular calcium concentration. Flow cytometry shows that knocking down T-type calcium channel expression with siRNA caused an increase in MCF-7 cells in G1 phase and a decrease in cells in S phase. Proliferation assays of MCF-7 cells treated with EGTA and thapsigargin reveal the dependence of MCF-7 cell growth on extracellular and intracellular calcium sources, respectively. In vitro, interlaced treatment that alternated the T-type calcium channel blocker NNC-55-0396 with paclitaxel more effectively reduced MCF-7 cell number than chemotherapy alone. In a mouse in vivo model, interlaced mibefradil and paclitaxel more effectively reduced MCF-7 xenograft size than chemotherapy alone. These findings indicate that MCF-7 cells are dependent on calcium for proliferation, particularly in passing the G1/S cell cycle checkpoint. Further, this dependence on calcium can be exploited by alternating treatment with T-type calcium channel blockers with paclitaxel in an interlaced therapy scheme that increases the efficacy of the chemotherapy.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

J. Pottle, C. Sun, L. Gray and M. Li, "Exploiting MCF-7 Cells’ Calcium Dependence with Interlaced Therapy," Journal of Cancer Therapy, Vol. 4 No. 7A, 2013, pp. 32-40. doi: 10.4236/jct.2013.47A006.


[1] H. L. Roderick and S. J. Cook, “Ca2+ Signaling Checkpoints in Cancer: Remodeling Ca2+ for Cancer Cell Proliferation and Survivial,” Nature Reviews Cancer, Vol. 8, No. 5, 2008, pp. 361-375. doi:10.1038/nrc2374
[2] D. Walker, T. Sun, S. MacNeil and R. Smallwood, “Modeling the Effect of Exogenous Calcium on Keratinocyte and HaCat Cell Proliferation and Differentiation Using and Agent-Based Computational Paradigm,” Tissue Engineering, Vol. 12, No. 8, 2006, pp. 2301-2309. doi:10.1089/ten.2006.12.2301
[3] S. Rosenberger, I. S. Thorey, S. Werner and P. Boukamp, “A Novel Regulator of Telomerase. S100A8 Mediates Differentiation-Dependent and Calcium-Induced Inhibition of Telomerase Activity in the Human Epidermal Keratinocyte Line HaCaT,” The Journal of Biological Chemistry, Vol. 282, No. 9, 2007, pp. 6126-6135. doi:10.1074/jbc.M610529200
[4] G. Legrand, S. Humez, C. Slomianny, E. Dewailly, F. Vanden Abeele, P. Mariot, F. Wuytack and N. Prevarskaya, “Ca2+ Pools and Cell Growth. Evidence for Sarcoendoplasmic Ca2+-ATPases 2B Involvement in Human Prostate Cancer Cell Growth Control,” The Journal of Biological Chemistry, Vol. 276, No. 50, 2001, pp. 47609-47614. doi:10.1074/jbc.M107011200
[5] V. Lehen’kyi, M. Flourakis, R. Skryma and N. Prevarskaya, “TRPV6 Channel Controls Prostate Cancer Cell Proliferation via Ca(2+)/NFAT-Dependent Pathways,” Oncogene, Vol. 26, No. 52, 2007, pp. 7380-7385. doi:10.1038/sj.onc.1210545
[6] J. T. Taylor, X. B. Zeng, J. E. Pottle, K. Lee, A. R. Wang, S. G. Yi, J. A. S. Scruggs, S. S. Sikka and M. Li, “Calcium Signaling and T-Type Calcium Channels in Cancer Cell Cycling,” World Journal of Gastroenterology, Vol. 14, No. 32, 2008, pp. 4984-4991. doi:10.3748/wjg.14.4984
[7] J. T. Taylor, L. Huang, J. E. Pottle, K. Liu, Y. Yang, X. Zeng, B. M. Keyser, K. C. Agrawal, J. B. Hansen and M. Li, “Selective Blockade of T-Type Ca2+ Channels Suppresses Human Breast Cancer Cell Proliferation,” Cancer Letters, Vol. 267, No. 1, 2008, pp. 116-124. doi:10.1016/j.canlet.2008.03.032
[8] F. Lu, H. Chen, C. Zhou, S. Liu, M. Guo, P. Chen, H. Zhuang, D. Xie and S. Wu, “T-Type Ca(2+) Channel Expression in Human Esophageal Carcinomas: A Functional Role in Proliferation,” Cell Calcium, Vol. 43, No. 1, 2008, pp. 49-58. doi:10.1016/j.ceca.2007.03.006
[9] G. E. Bertolesi, C. Shi, L. Elbaum, C. Jollimore, G. Rozenberg, S. Barnes and M. E. M. Kelly, “The Ca2+ Channel Antagonists Mibefradil and Pimozide Inhibit Cell Growth via Different Cytotoxic Mechanisms,” Molecular Pharmacology, Vol. 62, No. 2, 2002, pp. 210-219. doi:10.1124/mol.62.2.210
[10] A. Panner and R. D. Wurster, “T-Type Calcium Channels and Tumor Proliferation,” Cell Calcium, Vol. 40, No. 2, 2006, pp. 253-259. doi:10.1016/j.ceca.2006.04.029
[11] W. Li, S. L. Zhang, N. Wang, B. B. Zhang and M. Li, “Blockade of T-Type Ca2+ Channels Inhibits Human Ovarian Cancer Cell Proliferation,” Cancer Investigation, Vol. 29, No. 5, 2011, pp. 339-246. doi:10.3109/07357907.2011.568565
[12] A. Panner, L. L. Cribbs, G. M. Zainelli, T. C. Origitano, S. Singh and R. D. Wurster, “Variation of T-Type Calcium Channel Protein Expression Affects Cell Division of Cultured Tumor Cells,” Cell Calcium, Vol. 37, No. 2, 2005, pp. 105-119. doi:10.1016/j.ceca.2004.07.002
[13] P. Mariot, K. Vanoverberghe, N. Lalevee, M. F. Rossier and N. Prevarskaya, “Overexpression of an Alpha 1H (Cav3.2) T-Type Calcium Channel during Neuroendocrine Differentiation of Human Prostate Cancer Cells,” Journal of Biological Chemistry, Vol. 277, 2002, pp. 10824-10833. doi:10.1074/jbc.M108754200
[14] Y. Q. Wang, G. Brooks, C. B. Zhu, W. Z. Yuan, Y. Q. Li, and X. S. Wu, “Functional Analysis of the Human TType Calcium Channel Alpha 1H Subunit Gene in Cellular Proliferation,” Journal of Genetics & Genomics, Vol. 29, No. 8, 2002, pp. 659-665.
[15] J. F. Whitfield, A. L. Boynton, J. P. MacManus, R. H. Rixon, M. Sikorska, B. Tsang, P. R. Walker and S. H. Swierenga, “The Roles of Calcium and Cyclic AMP in Cell Proliferation,” Annals of the New York Academy of Sciences, Vol. 339, No. 1, 1980, pp. 216-240. doi:10.1111/j.1749-6632.1980.tb15980.x
[16] V. Crunelli, T. I. Toth, D. W. Cope, K. L. Blethyn and S. W. Hughes, “The ‘Window’ T-Type Current in Brain Dynamics of Different Behavioural States,” Journal of Physiology, Vol. 562, 2005, pp. 121-129. doi:10.1113/jphysiol.2004.076273
[17] J. F. Whitfield, “Calcium Signals and Cancer,” Critical Reviews in Oncogenesis, Vol. 3, No. 1-2, 1992, pp. 55-90.
[18] N. Dejeans, N. Tajeddine, R. Beck, J. Verrax, H. Taper, P. Gailly and P. B. Calderon, “Endoplasmic Reticulum Calcium Release Potentiates the ER Stress and Cell Death Caused by an Oxidative Stress in MCF-7 Cells,” Biochemical Pharmacology, Vol. 79, No. 9, 2010, pp. 1221-1230. doi:10.1016/j.bcp.2009.12.009
[19] C. Jackisch, H. A. Hahm, B. Tombal, D. McCloskey, K. Butash, N. E. Davidson and S. R. Denmeande, “Delayed Micromolar Elevation in Intracellular Calcium Precedes Induction of Apoptosis in Thapsigargin-treated Breast Cancer Cells,” Clinical Cancer Research, Vol. 6, 2000, pp. 2844-2850.
[20] S. Wu, M. Zhang, P. A. Vest, A. Bhattacharjee, L. Liu and M. Li, “A Mibefradil Metabolite Is a Potent Intracellular Blocker of L-Type Ca2+ Currents in Pancreatic β-Cells,” The Journal of Pharmacology and Experimental Therapeutics, Vol. 292, No. 3, 2000, pp. 939-943.

comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.