Selective blockade of T-type Ca2+ channels suppresses human breast cancer cell proliferation

Taylor, James T.; Huang, Lüping; Pottle, Jonathan E.; Yang, Yong; Zeng, Xianyi; Keyser, Brian M.; Agrawal, Krishna C.; Hansen, John Bondo; Li, Ming

doi:10.1016/j.canlet.2008.03.032

Cited by 105 publications

(103 citation statements)

References 30 publications

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“…Expression of these channels in tumor cells has been reported broadly, as shown in Table 1 [1, [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] . For example, MCF-7 cells, a cell line derived from a human breast adenocarcinoma that has been shown to express α 1G and α 1H T-type Ca 2+ channel mRNA and current transiently (Table 2) [33] . T-type Ca 2+ channels have also been suggested as a potential therapeutic target for intracranial tumor and prostate cancer.…”

Section: T-type Camentioning

confidence: 99%

Calcium signaling and T-type calcium channels in cancer cell cycling

Taylor¹,

Zeng²,

Pottle³

et al. 2008

WJG

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141

108

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Regulation of intracellular calcium is an important signaling mechanism for cell proliferation in both normal and cancerous cells. In normal epithelial cells, free calcium concentration is essential for cells to enter and accomplish the S phase and the M phase of the cell cycle. In contrast, cancerous cells can pass these phases of the cell cycle with much lower cytoplasmic free calcium concentrations, indicating an alternative mechanism has developed for fulfilling the intracellular calcium requirement for an increased rate of DNA synthesis and mitosis of fast replicating cancerous cells. The detailed mechanism underlying the altered calcium loading pathway remains unclear; however, there is a growing body of evidence that suggests the T-type Ca 2+ channel is abnormally expressed in cancerous cells and that blockade of these channels may reduce cell proliferation in addition to inducing apoptosis. Recent studies also show that the expression of T-type Ca 2+ channels in breast cancer cells is proliferation state dependent, i.e. the channels are expressed at higher levels during the fast-replication period, and once the cells are in a non-proliferation state, expression of this channel is minimal. Therefore, selectively blocking calcium entry into cancerous cells may be a valuable approach for preventing tumor growth. Since T-type Ca 2+ channels are not expressed in epithelial cells, selective T-type Ca 2+ channel blockers may be useful in the treatment of certain types of cancers.

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Section: T-type Camentioning

confidence: 99%

Calcium signaling and T-type calcium channels in cancer cell cycling

Taylor¹,

Zeng²,

Pottle³

et al. 2008

WJG

Self Cite

141

108

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show abstract

“…Voltage gated Ca 2þ channels facilitate transient Ca 2þ influx from the environment into the cytoplasm and appear mostly in excitable tissues, but also are unusually expressed in cancer cells. Low-voltage activated Ca 2þ channels, termed T-type Ca 2þ channels, recently gained attention in cancer therapy, because their inhibition decreased proliferation of glioblastoma cells (3,4), breast adenocarcinoma cells (5,6), melanoma cells (7), and esophageal carcinoma cells (8). In addition, an antagonist selective for T-type Ca 2þ channels, mibefradil, has been proposed recently as a sensitizing agent with activity in vivo in combination with chemo-(9) or radiotherapy (10).…”

Section: Introductionmentioning

confidence: 99%

T-Type Ca2+ Channel Inhibition Induces p53-Dependent Cell Growth Arrest and Apoptosis through Activation of p38-MAPK in Colon Cancer Cells

Dziegielewska

Brautigan

Larner

et al. 2014

Molecular Cancer Research

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Epithelial tumor cells express T-type Ca 2þ channels, which are thought to promote cell proliferation. This study investigated the cellular response to T-type Ca 2þ channel inhibition either by small-molecule antagonists or by RNAi-mediated knockdown. Selective T-type Ca 2þ channel antagonists caused growth inhibition and apoptosis more effectively in HCT116 cells expressing wild-type p53 (p53wt), than in HCT116 mutant p53 À/À cells. These antagonists increased p53-dependent gene expression and increased genomic occupancy of p53 at specific target sequences. The knockdown of a single T-type Ca 2þ channel subunit (CACNA1G) reduced cell growth and induced caspase-3/7 activation in HCT116 p53wt cells as compared with HCT116 mutant p53 À/À cells. Moreover, CaCo2 cells that do not express functional p53 were made more sensitive to CACNA1G knockdown when p53wt was stably expressed. Upon T-type Ca 2þ channel inhibition, p38-MAPK promoted phosphorylation at Ser392 of p53wt. Cells treated with the inhibitor SB203580 or specific RNAi targeting p38-MAPKa/b (MAPK14/MAPK11) showed resistance to T-type Ca 2þ channel inhibition. Finally, the decreased sensitivity to channel inhibition was associated with decreased accumulation of p53 and decreased expression of p53 target genes, p21Cip1 (CDKN1A) and BCL2-binding component 3 (BBC3/PUMA).

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“…In previous studies, T-type channel blockers such as mibefradil and pimozide, which cannot distinguish between Ca v 3.1 and Ca v 3.2 channels, were used to investigate the regulation of cancer cell proliferation (13)(14)(15)(16)(17). Since there is a possibility that these isoforms exhibit different functions in tumors, if both isoforms are inhibited by such drugs to the same extent, the results should be interpreted with caution.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in prostate carcinoma cells, an increase in T-type Ca v 3.1 channel expression has been found to correlate with the inhibition of proliferation and the promotion of apoptosis (12). Alternatively, a number of reports have speculated on the progressive roles of T-type channels in tumor growth (13)(14)(15)(16). In addition to such conflicts, almost all these reports have not distinguished among T-type isoforms, since the currently available blockers that have been used have poor specificities for each isoform.…”

Section: Introductionmentioning

confidence: 99%