Breast Cancer Research and Treatment

, Volume 173, Issue 1, pp 11–21 | Cite as

T-Type voltage gated calcium channels: a target in breast cancer?

  • Anamika BhargavaEmail author
  • Sumit Saha



The purpose of this review article is to discuss the potential of T-type voltage gated calcium channels (VGCCs) as drug targets in breast cancer.


Breast cancer, attributable to the different molecular subtypes, has a crucial need for therapeutic strategies to counter the mortality rate. VGCCs play an important role in regulating cytosolic free calcium levels which regulate cellular processes like tumorigenesis and cancer progression. In the last decade, T-type VGCCs have been investigated in breast cancer proliferation. Calcium channel blockers, in general, have shown an anti-proliferative and cytotoxic effects. T-type VGCC antagonists have shown growth inhibition owing to the inhibition of CaV3.2 isoform. CaV3.1 isoform has been indicated as a tumour-suppressor gene candidate and is reported to support anti-proliferative and apoptotic activity in breast cancer. The distribution of T-type VGCC isoforms in different breast cancer molecular subtypes is diverse and needs to be further investigated. The role of T-type VGCCs in breast cancer migration, metastasis and more importantly in epithelial to mesenchymal transition (EMT) is yet to be elucidated. In addition, interlaced therapy, using a combination of chemotherapy drugs and T-type VGCC blockers, presents a promising therapeutic approach for breast cancer but more validation and clinical trials are needed. Also, for investigating the potential of T-type VGCC blocker therapy, there is a need for isoform-specific agonists/antagonists to define and discover roles of T-type VGCC specific isoforms.


Our article provides a review of the role of T-type VGCCs in breast cancer and also discusses future of the research in this area so that it can be ascertained whether there is any potential of T-type VGCCs as drug targets in breast cancer.


Breast cancer Voltage gated calcium channel T-type VGCCs Calcium influx 



This work was supported by grants to AB: BioCARe, DBT, India, (BT/BioCARe/01/9701/2013-14), seed grant, IITH (SG/IITH/F145/2016-17/SG-27), ECR SERB-DST (ECR/2017/000242) and MHRD, India fellowship to SH.

Compliance with ethical standards

Conflict of interest

The authors declare having no financial competing interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4(7):517–529. Google Scholar
  2. 2.
    Carafoli E, Santella L, Branca D, Brini M (2001) Generation, control, and processing of cellular calcium signals. Crit Rev Biochem Mol Biol 36(2):107–260. Google Scholar
  3. 3.
    Bowie D (2012) Ligand-gated ion channels: from genes to behaviour. J Physiol 590(1):9–11. Google Scholar
  4. 4.
    North RA (2016) P2X receptors. Philos Trans R Soc Lond B Biol Sci 371 (1700).
  5. 5.
    Thompson AJ, Lummis SC (2006) 5-HT3 receptors. Curr Pharm Des 12(28):3615–3630Google Scholar
  6. 6.
    Hille B (1978) Ionic channels in excitable membranes. Current problems and biophysical approaches. Biophys J 22(2):283–294. Google Scholar
  7. 7.
    Prakriya M, Lewis RS (2015) Store-Operated calcium channels. Physiol Rev 95(4):1383–1436. Google Scholar
  8. 8.
    Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E, Schwartz A, Snutch TP, Tanabe T, Birnbaumer L, Tsien RW, Catterall WA (2000) Nomenclature of voltage-gated calcium channels. Neuron 25(3):533–535Google Scholar
  9. 9.
    Catterall WA (2010) Signaling complexes of voltage-gated sodium and calcium channels. Neurosci Lett 486(2):107–116. Google Scholar
  10. 10.
    Bidaud I, Mezghrani A, Swayne LA, Monteil A, Lory P (2006) Voltage-gated calcium channels in genetic diseases. Biochim Biophys Acta 1763(11):1169–1174. Google Scholar
  11. 11.
    Prevarskaya N, Skryma R, Shuba Y (2010) Ion channels and the hallmarks of cancer. Trends Mol Med 16(3):107–121. Google Scholar
  12. 12.
    Phan NN, Wang CY, Chen CF, Sun Z, Lai MD, Lin YC (2017) Voltage-gated calcium channels: novel targets for cancer therapy. Oncol Lett 14(2):2059–2074. Google Scholar
  13. 13.
    Gray LS, Macdonald TL (2006) The pharmacology and regulation of T type calcium channels: new opportunities for unique therapeutics for cancer. Cell Calcium 40(2):115–120. Google Scholar
  14. 14.
    Panner A, Wurster RD (2006) T-type calcium channels and tumor proliferation. Cell Calcium 40(2):253–259. Google Scholar
  15. 15.
    Taylor JT, Zeng XB, Pottle JE, Lee K, Wang AR, Yi SG, Scruggs JA, Sikka SS, Li M (2008) Calcium signaling and T-type calcium channels in cancer cell cycling. World J Gastroenterol 14(32):4984–4991Google Scholar
  16. 16.
    Hagiwara S, Ozawa S, Sand O (1975) Voltage clamp analysis of two inward current mechanisms in the egg cell membrane of a starfish. J Gen Physiol 65(5):617–644Google Scholar
  17. 17.
    Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83(1):117–161. Google Scholar
  18. 18.
    Hofmann F, Belkacemi A, Flockerzi V (2015) Emerging Alternative Functions for the Auxiliary Subunits of the Voltage-Gated Calcium Channels. Curr Mol Pharmacol 8(2):162–168Google Scholar
  19. 19.
    Li M, Hansen JB, Huang L, Keyser BM, Taylor JT (2005) Towards selective antagonists of T-type calcium channels: design, characterization and potential applications of NNC 55–0396. Cardiovasc Drug Rev 23(2):173–196Google Scholar
  20. 20.
    Cain SM, Snutch TP (2010) Contributions of T-type calcium channel isoforms to neuronal firing. Channels (Austin) 4(6):475–482. Google Scholar
  21. 21.
    Hagiwara N, Irisawa H, Kameyama M (1988) Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol 395:233–253Google Scholar
  22. 22.
    Huc S, Monteil A, Bidaud I, Barbara G, Chemin J, Lory P (2009) Regulation of T-type calcium channels: signalling pathways and functional implications. Biochim Biophys Acta 1793(6):947–952. Google Scholar
  23. 23.
    Oguri A, Tanaka T, Iida H, Meguro K, Takano H, Oonuma H, Nishimura S, Morita T, Yamasoba T, Nagai R, Nakajima T (2010) Involvement of CaV3.1 T-type calcium channels in cell proliferation in mouse preadipocytes. Am J Physiol Cell Physiol 298(6):C1414–C1423. Google Scholar
  24. 24.
    Ono K, Iijima T (2010) Cardiac T-type Ca(2+) channels in the heart. J Mol Cell Cardiol 48(1):65–70. Google Scholar
  25. 25.
    Weiss N, Zamponi GW (2013) Control of low-threshold exocytosis by T-type calcium channels. Biochim Biophys Acta 1828(7):1579–1586. Google Scholar
  26. 26.
    Nelson MT, Todorovic SM, Perez-Reyes E (2006) The role of T-type calcium channels in epilepsy and pain. Curr Pharm Des 12(18):2189–2197Google Scholar
  27. 27.
    Bourinet E, Francois A, Laffray S (2016) T-type calcium channels in neuropathic pain. Pain 157 Suppl 1:S15–S22.
  28. 28.
    Dziegielewska B, Casarez EV, Yang WZ, Gray LS, Dziegielewski J, Slack-Davis JK (2016) T-Type Ca2 + Channel Inhibition Sensitizes Ovarian Cancer to Carboplatin. Mol Cancer Ther 15(3):460–470. Google Scholar
  29. 29.
    Gackiere F, Bidaux G, Delcourt P, Van Coppenolle F, Katsogiannou M, Dewailly E, Bavencoffe A, Van Chuoi-Mariot MT, Mauroy B, Prevarskaya N, Mariot P (2008) CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells. J Biol Chem 283(15):10162–10173. Google Scholar
  30. 30.
    Hayashi K, Homma K, Wakino S, Tokuyama H, Sugano N, Saruta T, Itoh H (2010) T-type Ca channel blockade as a determinant of kidney protection. Keio J Med 59(3):84–95Google Scholar
  31. 31.
    Huang W, Lu C, Wu Y, Ouyang S, Chen Y (2015) T-type calcium channel antagonists, mibefradil and NNC-55-0396 inhibit cell proliferation and induce cell apoptosis in leukemia cell lines. J Exp Clin Cancer Res 34:54. Google Scholar
  32. 32.
    Maiques O, Macia A, Moreno S, Barcelo C, Santacana M, Vea A, Herreros J, Gatius S, Ortega E, Valls J, Chen BJ, Llobet-Navas D, Matias-Guiu X, Canti C, Marti RM (2017) Immunohistochemical analysis of T-type calcium channels in acquired melanocytic naevi and melanoma. Br J Dermatol 176(5):1247–1258. Google Scholar
  33. 33.
    Taylor JT, Huang L, Pottle JE, Liu K, Yang Y, Zeng X, Keyser BM, Agrawal KC, Hansen JB, Li M (2008) Selective blockade of T-type Ca2 + channels suppresses human breast cancer cell proliferation. Cancer Lett 267(1):116–124. Google Scholar
  34. 34.
    Toyota M, Ho C, Ohe-Toyota M, Baylin SB, Issa JP (1999) Inactivation of CACNA1G, a T-type calcium channel gene, by aberrant methylation of its 5′ CpG island in human tumors. Cancer Res 59(18):4535–4541Google Scholar
  35. 35.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. Google Scholar
  36. 36.
    Gupta A, Shridhar K, Dhillon PK (2015) A review of breast cancer awareness among women in India: cancer literate or awareness deficit? Eur J Cancer 51(14):2058–2066. Google Scholar
  37. 37.
    Yersal O, Barutca S (2014) Biological subtypes of breast cancer: prognostic and therapeutic implications. World J Clin Oncol 5(3):412–424. Google Scholar
  38. 38.
    Bao T, Davidson NE (2008) Gene expression profiling of breast cancer. Adv Surg 42:249–260Google Scholar
  39. 39.
    Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J, Shi B (2015) Breast cancer intrinsic subtype classification, clinical use and future trends. Am J Cancer Res 5(10):2929–2943Google Scholar
  40. 40.
    Spitale A, Mazzola P, Soldini D, Mazzucchelli L, Bordoni A (2009) Breast cancer classification according to immunohistochemical markers: clinicopathologic features and short-term survival analysis in a population-based study from the South of Switzerland. Ann Oncol 20(4):628–635. Google Scholar
  41. 41.
    Weigelt B, Baehner FL, Reis-Filho JS (2010) The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade. J Pathol 220(2):263–280. Google Scholar
  42. 42.
    Zardavas D, Irrthum A, Swanton C, Piccart M (2015) Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol 12(7):381–394. Google Scholar
  43. 43.
    Hendrick RE, Smith RA, Rutledge JH 3rd, Smart CR (1997) Benefit of screening mammography in women aged 40–49: a new meta-analysis of randomized controlled trials. J Natl Cancer Inst Monogr (22):87–92Google Scholar
  44. 44.
    Breast International Group 1–98 Collaborative G, Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353 (26):2747–2757. Google Scholar
  45. 45.
    Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF, investigators AL (2010) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 11(12):1135–1141. Google Scholar
  46. 46.
    Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, Correa C, Cutter D, Gagliardi G, Gigante B, Jensen MB, Nisbet A, Peto R, Rahimi K, Taylor C, Hall P (2013) Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 368(11):987–998. Google Scholar
  47. 47.
    Early Breast Cancer Trialists’ Collaborative G (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365(9472):1687–1717. Google Scholar
  48. 48.
    Early Breast Cancer Trialists’ Collaborative G, Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, Cutter D, Davies C, Ewertz M, Godwin J, Gray R, Pierce L, Whelan T, Wang Y, Peto R (2011) Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378 (9804):1707–1716. Google Scholar
  49. 49.
    Kaplan HG, Malmgren JA, Atwood MK (2011) Increased incidence of myelodysplastic syndrome and acute myeloid leukemia following breast cancer treatment with radiation alone or combined with chemotherapy: a registry cohort analysis 1990–2005. BMC Cancer 11:260. Google Scholar
  50. 50.
    Tassone P, Tagliaferri P, Perricelli A, Blotta S, Quaresima B, Martelli ML, Goel A, Barbieri V, Costanzo F, Boland CR, Venuta S (2003) BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells. Br J Cancer 88(8):1285–1291. Google Scholar
  51. 51.
    Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Dieras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K, Group ES (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367(19):1783–1791. Google Scholar
  52. 52.
    Wahba HA, El-Hadaad HA (2015) Current approaches in treatment of triple-negative breast cancer. Cancer Biol Med 12(2):106–116. Google Scholar
  53. 53.
    Velaei K, Samadi N, Barazvan B, Soleimani Rad J (2016) Tumor microenvironment-mediated chemoresistance in breast cancer. Breast 30:92–100. Google Scholar
  54. 54.
    Kim C, Lee J, Lee W, Kim A (2015) Changes in intrinsic subtype of breast cancer during tumor progression in the same patient. Int J Clin Exp Pathol 8(11):15184–15190Google Scholar
  55. 55.
    Curigliano G, Criscitiello C (2014) Successes and limitations of targeted cancer therapy in breast cancer. Prog Tumor Res 41:15–35. Google Scholar
  56. 56.
    Azimi I, Roberts-Thomson SJ, Monteith GR (2014) Calcium influx pathways in breast cancer: opportunities for pharmacological intervention. Br J Pharmacol 171(4):945–960. Google Scholar
  57. 57.
    Buchanan PJ, McCloskey KD (2016) CaV channels and cancer: canonical functions indicate benefits of repurposed drugs as cancer therapeutics. Eur Biophys J 45(7):621–633. Google Scholar
  58. 58.
    Hayashi K, Wakino S, Sugano N, Ozawa Y, Homma K, Saruta T (2007) Ca2 + channel subtypes and pharmacology in the kidney. Circ Res 100(3):342–353. Google Scholar
  59. 59.
    Santoni G, Santoni M, Nabissi M (2012) Functional role of T-type calcium channels in tumour growth and progression: prospective in cancer therapy. Br J Pharmacol 166(4):1244–1246. Google Scholar
  60. 60.
    Zhou C, Wu S (2006) T-type calcium channels in pulmonary vascular endothelium. Microcirculation 13(8):645–656. Google Scholar
  61. 61.
    Pahor M, Guralnik JM, Ferrucci L, Corti MC, Salive ME, Cerhan JR, Wallace RB, Havlik RJ (1996) Calcium-channel blockade and incidence of cancer in aged populations. Lancet 348(9026):493–497. Google Scholar
  62. 62.
    Fitzpatrick AL, Daling JR, Furberg CD, Kronmal RA, Weissfeld JL (1997) Use of calcium channel blockers and breast carcinoma risk in postmenopausal women. Cancer 80(8):1438–1447Google Scholar
  63. 63.
    Bergman GJ, Khan S, Danielsson B, Borg N (2014) Breast cancer risk and use of calcium channel blockers using Swedish population registries. JAMA Intern Med 174(10):1700–1701. Google Scholar
  64. 64.
    Devore EE, Kim S, Ramin CA, Wegrzyn LR, Massa J, Holmes MD, Michels KB, Tamimi RM, Forman JP, Schernhammer ES (2015) Antihypertensive medication use and incident breast cancer in women. Breast Cancer Res Treat 150(1):219–229. Google Scholar
  65. 65.
    Fryzek JP, Poulsen AH, Lipworth L, Pedersen L, Norgaard M, McLaughlin JK, Friis S (2006) A cohort study of antihypertensive medication use and breast cancer among Danish women. Breast Cancer Res Treat 97(3):231–236. Google Scholar
  66. 66.
    Meier CR, Derby LE, Jick SS, Jick H (2000) Angiotensin-converting enzyme inhibitors, calcium channel blockers, and breast cancer. Arch Intern Med 160(3):349–353Google Scholar
  67. 67.
    Michels KB, Rosner BA, Walker AM, Stampfer MJ, Manson JE, Colditz GA, Hennekens CH, Willett WC (1998) Calcium channel blockers, cancer incidence, and cancer mortality in a cohort of U.S. women: the nurses’ health study. Cancer 83(9):2003–2007Google Scholar
  68. 68.
    Olsen JH, Sorensen HT, Friis S, McLaughlin JK, Steffensen FH, Nielsen GL, Andersen M, Fraumeni JF Jr, Olsen J (1997) Cancer risk in users of calcium channel blockers. Hypertension 29(5):1091–1094Google Scholar
  69. 69.
    Rosenberg L, Rao RS, Palmer JR, Strom BL, Stolley PD, Zauber AG, Warshauer ME, Shapiro S (1998) Calcium channel blockers and the risk of cancer. JAMA 279(13):1000–1004Google Scholar
  70. 70.
    Ye X, Du Q, Li H, Yu B, Zhai Q (2016) Calcium channel blockers and risk of breast cancer: a meta-analysis. Int J Clin Exp Med 9(10):20425–20431Google Scholar
  71. 71.
    Wilson LE, D’Aloisio AA, Sandler DP, Taylor JA (2016) Long-term use of calcium channel blocking drugs and breast cancer risk in a prospective cohort of US and Puerto Rican women. Breast Cancer Res 18(1):61. Google Scholar
  72. 72.
    Bertolesi GE, Shi C, Elbaum L, Jollimore C, Rozenberg G, Barnes S, Kelly ME (2002) The Ca(2+) channel antagonists mibefradil and pimozide inhibit cell growth via different cytotoxic mechanisms. Mol Pharmacol 62(2):210–219Google Scholar
  73. 73.
    Gray LS, Perez-Reyes E, Gomora JC, Haverstick DM, Shattock M, McLatchie L, Harper J, Brooks G, Heady T, Macdonald TL (2004) The role of voltage gated T-type Ca2 + channel isoforms in mediating “capacitative” Ca2+ entry in cancer cells. Cell Calcium 36(6):489–497. Google Scholar
  74. 74.
    Asaga S, Ueda M, Jinno H, Kikuchi K, Itano O, Ikeda T, Kitajima M (2006) Identification of a new breast cancer-related gene by restriction landmark genomic scanning. Anticancer Res 26(1A):35–42Google Scholar
  75. 75.
    Hayashizaki Y, Hirotsune S, Okazaki Y, Hatada I, Shibata H, Kawai J, Hirose K, Watanabe S, Fushiki S, Wada S et al (1993) Restriction landmark genomic scanning method and its various applications. Electrophoresis 14(4):251–258Google Scholar
  76. 76.
    Yoshida M, Nosaka K, Yasunaga J, Nishikata I, Morishita K, Matsuoka M (2004) Aberrant expression of the MEL1S gene identified in association with hypomethylation in adult T-cell leukemia cells. Blood 103(7):2753–2760. Google Scholar
  77. 77.
    McCalmont WF, Heady TN, Patterson JR, Lindenmuth MA, Haverstick DM, Gray LS, Macdonald TL (2004) Design, synthesis, and biological evaluation of novel T-Type calcium channel antagonists. Bioorg Med Chem Lett 14(14):3691–3695. Google Scholar
  78. 78.
    Pottle J, Sun C, Gray L, Li M (2013) Exploiting MCF-7 cells’ calcium dependence with interlaced therapy. Journal of Cancer Therapy 4(7A):32–40. Google Scholar
  79. 79.
    Dziegielewska B, Gray LS, Dziegielewski J (2014) T-type calcium channels blockers as new tools in cancer therapies. Pflugers Arch 466(4):801–810. Google Scholar
  80. 80.
    Ohkubo T, Yamazaki J (2012) T-type voltage-activated calcium channel Cav3.1, but not Cav3.2, is involved in the inhibition of proliferation and apoptosis in MCF-7 human breast cancer cells. Int J Oncol 41(1):267–275. Google Scholar
  81. 81.
    Ranzato E, Magnelli V, Martinotti S, Waheed Z, Cain SM, Snutch TP, Marchetti C, Burlando B (2014) Epigallocatechin-3-gallate elicits Ca2 + spike in MCF-7 breast cancer cells: essential role of Cav3.2 channels. Cell Calcium 56(4):285–295. Google Scholar
  82. 82.
    Basson MD, Zeng B, Downey C, Sirivelu MP, Tepe JJ (2015) Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC-beta. Mol Oncol 9(2):513–526. Google Scholar
  83. 83.
    Pera E, Kaemmerer E, Milevskiy MJG, Yapa K, O’Donnell JS, Brown MA, Simpson F, Peters AA, Roberts-Thomson SJ, Monteith GR (2016) The voltage gated Ca(2+)-channel Cav3.2 and therapeutic responses in breast cancer. Cancer Cell Int 16:24. Google Scholar
  84. 84.
    Li W, Zhang SL, Wang N, Zhang BB, Li M (2011) Blockade of T-type Ca(2+) channels inhibits human ovarian cancer cell proliferation. Cancer Invest 29(5):339–346. Google Scholar
  85. 85.
    Dziegielewska B, Brautigan DL, Larner JM, Dziegielewski J (2014) T-type Ca2 + channel inhibition induces p53-dependent cell growth arrest and apoptosis through activation of p38-MAPK in colon cancer cells. Mol Cancer Res 12(3):348–358. Google Scholar
  86. 86.
    Zhang Y, Wang H, Qian Z, Feng B, Zhao X, Jiang X, Tao J (2014) Low-voltage-activated T-type Ca2+ channel inhibitors as new tools in the treatment of glioblastoma: the role of endostatin. Pflugers Arch 466(4):811–818. Google Scholar
  87. 87.
    Valerie NC, Dziegielewska B, Hosing AS, Augustin E, Gray LS, Brautigan DL, Larner JM, Dziegielewski J (2013) Inhibition of T-type calcium channels disrupts Akt signaling and promotes apoptosis in glioblastoma cells. Biochem Pharmacol 85(7):888–897. Google Scholar
  88. 88.
    Chou YS, Yang MH (2015) Epithelial-mesenchymal transition-related factors in solid tumor and hematological malignancy. J Chin Med Assoc 78(8):438–445. Google Scholar
  89. 89.
    Deng J, Wang L, Chen H, Hao J, Ni J, Chang L, Duan W, Graham P, Li Y (2016) Targeting epithelial-mesenchymal transition and cancer stem cells for chemoresistant ovarian cancer. Oncotarget 7(34):55771–55788. Google Scholar
  90. 90.
    Marcucci F, Stassi G, De Maria R (2016) Epithelial-mesenchymal transition: a new target in anticancer drug discovery. Nat Rev Drug Discov 15(5):311–325. Google Scholar
  91. 91.
    Nassar D, Blanpain C (2016) Cancer stem cells: basic concepts and therapeutic implications. Annu Rev Pathol 11:47–76. Google Scholar
  92. 92.
    Papaccio F, Paino F, Regad T, Papaccio G, Desiderio V, Tirino V (2017) Concise review: cancer cells, cancer stem cells, and mesenchymal stem cells: influence in cancer development. Stem Cells Transl Med 6(12):2115–2125. Google Scholar
  93. 93.
    Brabletz T, Kalluri R, Nieto MA, Weinberg RA (2018) EMT in cancer. Nat Rev Cancer 18(2):128–134. Google Scholar
  94. 94.
    Heerboth S, Housman G, Leary M, Longacre M, Byler S, Lapinska K, Willbanks A, Sarkar S (2015) EMT and tumor metastasis. Clin Transl Med 4:6. Google Scholar
  95. 95.
    Bringmann A, Schopf S, Reichenbach A (2000) Developmental regulation of calcium channel-mediated currents in retinal glial (Muller) cells. J Neurophysiol 84(6):2975–2983. Google Scholar
  96. 96.
    Rodriguez-Gomez JA, Levitsky KL, Lopez-Barneo J (2012) T-type Ca2+ channels in mouse embryonic stem cells: modulation during cell cycle and contribution to self-renewal. Am J Physiol Cell Physiol 302(3):C494–C504. Google Scholar
  97. 97.
    Jacquemet G, Baghirov H, Georgiadou M, Sihto H, Peuhu E, Cettour-Janet P, He T, Perala M, Kronqvist P, Joensuu H, Ivaska J (2016) L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling. Nat Commun 7:13297. Google Scholar
  98. 98.
    Hirooka K, Bertolesi GE, Kelly ME, Denovan-Wright EM, Sun X, Hamid J, Zamponi GW, Juhasz AE, Haynes LW, Barnes S (2002) T-Type calcium channel alpha1G and alpha1H subunits in human retinoblastoma cells and their loss after differentiation. J Neurophysiol 88(1):196–205. Google Scholar
  99. 99.
    Palmieri C, Rudraraju B, Monteverde M, Lattanzio L, Gojis O, Brizio R, Garrone O, Merlano M, Syed N, Lo Nigro C, Crook T (2012) Methylation of the calcium channel regulatory subunit alpha2delta-3 (CACNA2D3) predicts site-specific relapse in oestrogen receptor-positive primary breast carcinomas. Br J Cancer 107(2):375–381. Google Scholar
  100. 100.
    Gray LS, Schiff D, Macdonald TL (2013) A model for the regulation of T-type Ca(2+) channels in proliferation: roles in stem cells and cancer. Expert Rev Anticancer Ther 13(5):589–595. Google Scholar
  101. 101.
    Haverstick DM, Heady TN, Macdonald TL, Gray LS (2000) Inhibition of human prostate cancer proliferation in vitro and in a mouse model by a compound synthesized to block Ca2+ entry. Cancer Res 60(4):1002–1008Google Scholar
  102. 102.
    Zhang Y, Cruickshanks N, Yuan F, Wang B, Pahuski M, Wulfkuhle J, Gallagher I, Koeppel AF, Hatef S, Papanicolas C, Lee J, Bar EE, Schiff D, Turner SD, Petricoin EF, Gray LS, Abounader R (2017) Targetable T-type calcium channels drive glioblastoma. Cancer Res 77(13):3479–3490. Google Scholar
  103. 103.
    Cove-Smith A, Mulgrew CJ, Rudyk O, Dutt N, McLatchie LM, Shattock MJ, Hendry BM (2013) Anti-proliferative actions of T-type calcium channel inhibition in Thy1 nephritis. Am J Pathol 183(2):391–401. Google Scholar
  104. 104.
    Keir ST, Friedman HS, Reardon DA, Bigner DD, Gray LA (2013) Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model. J Neurooncol 111(2):97–102. Google Scholar
  105. 105.
    Mulgrew CJ, Cove-Smith A, McLatchie LM, Brooks G, Shattock MJ, Hendry BM (2009) Inhibition of human mesangial cell proliferation by targeting T-type calcium channels. Nephron Exp Nephrol 113(2):e77–e88. Google Scholar
  106. 106.
    Krouse AJ, Gray L, Macdonald T, McCray J (2015) Repurposing and rescuing of mibefradil, an antihypertensive, for cancer: a case study. Assay Drug Dev Technol 13(10):650–653. Google Scholar
  107. 107.
    Holdhoff M, Ye X, Supko JG, Nabors LB, Desai AS, Walbert T, Lesser GJ, Read WL, Lieberman FS, Lodge MA, Leal J, Fisher JD, Desideri S, Grossman SA, Wahl RL, Schiff D (2017) Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas. Neuro Oncol 19(6):845–852. Google Scholar
  108. 108.
    McCalmont WF, Patterson JR, Lindenmuth MA, Heady TN, Haverstick DM, Gray LS, Macdonald TL (2005) Investigation into the structure-activity relationship of novel concentration dependent, dual action T-type calcium channel agonists/antagonists. Bioorg Med Chem 13(11):3821–3839. Google Scholar
  109. 109.
    Marger F, Gelot A, Alloui A, Matricon J, Ferrer JF, Barrere C, Pizzoccaro A, Muller E, Nargeot J, Snutch TP, Eschalier A, Bourinet E, Ardid D (2011) T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome. Proc Natl Acad Sci USA 108(27):11268–11273. Google Scholar
  110. 110.
    Bui PH, Quesada A, Handforth A, Hankinson O (2008) The mibefradil derivative NNC55-0396, a specific T-type calcium channel antagonist, exhibits less CYP3A4 inhibition than mibefradil. Drug Metab Dispos 36(7):1291–1299. Google Scholar
  111. 111.
    Denmeade SR, Mhaka AM, Rosen DM, Brennen WN, Dalrymple S, Dach I, Olesen C, Gurel B, Demarzo AM, Wilding G, Carducci MA, Dionne CA, Moller JV, Nissen P, Christensen SB, Isaacs JT (2012) Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy. Sci Transl Med 4(140):140ra186. Google Scholar
  112. 112.
    Kale VP, Amin SG, Pandey MK (2015) Targeting ion channels for cancer therapy by repurposing the approved drugs. Biochim Biophys Acta 1848(10 Pt B):2747–2755. Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Ion Channel Biology Lab, Department of BiotechnologyIndian Institute of Technology Hyderabad (IITH)KandiIndia

Personalised recommendations