T-type Ca2+ Channels: T for Targetable

Abstract

In the past decade, T-type Ca channels (TTCC) have been unveiled as key regulators of cancer cell biology and thus have been proposed as chemotherapeutic targets. Indeed, and studies indicate that TTCC pharmacologic blockers have a negative impact on the viability of cancer cells and reduce tumor size, respectively. Consequently mibefradil, a TTCC blocker approved in 1997 as an antihypertensive agent but withdrawn in 1998 because of drug-drug interactions, was granted 10 years later the orphan drug status by the FDA to investigate its efficacy against brain, ovary, and pancreatic cancer. However, the existence of different channel isoforms with distinct physiologic roles, together with the lack of selective pharmacologic agents, has hindered a conclusive chemotherapeutic evaluation. Here, we review the available evidence on TTCC expression, value as prognostic markers, and effectiveness of their pharmacologic blockade on cancer cells and in preclinical models. We additionally summarize the status of clinical trials using mibefradil against glioblastoma multiforme. Finally, we discuss the future perspectives and the importance of further development of multidisciplinary research efforts on the consideration of TTCCs as biomarkers or targetable molecules in cancer..

T‐type calcium channels drive the proliferation of androgen‐receptor negative prostate cancer cells

“…Our analysis indicates that CACNA1G expression is progressively upregulated in CRPC and NEPC samples, and that higher CACNA1G expression levels predict poorer prognosis in earlier stages of the disease. These data are in accordance with the observation that TTCCs are generally unregulated in the majority of PCa samples …”

“…These data are in accordance with the observation that TTCCs are generally unregulated in the majority of PCa samples. 15,16…”

“…Probably, both pharmacological antagonists and the specific siRNA exerted these effects of PC-3 cells by activating the p38-MAPK pathway through an upregulation of p53 as already observed in other cell lines (as reviewed by Sallan eMet al). 15 Nonetheless, further experiments will be necessary to evaluate this hypothesis and to extend our observations to a larger panel of PCa cell lines.…”

Targeting Calcium Signalling in Malignant Mesothelioma

“…Recent literature have discussed the idea of pharmacological inhibition or RNAi-mediated downregulation of T-type Ca 2+ channels as a way to inhibit cancer cell growth and increase cancer cell death [42]. In addition to a single agent activity, the results validate that T-type Ca 2+ channel blockers improve the anticancer properties of conventional radio-and chemotherapy [43]. Consequently, T-type Ca 2+ channels could be attractive molecular targets for the improvement of mesothelioma treatment, considering the actual inefficacy of classic therapy.…”

“…Increased expression of AKT, BCL-2, and BCL2L1 was found, whereas the expression of PML, a suppressor of oncogenesis, was reduced. They also found a reduced level of the Mitochondrial Calcium Uniporter (MCU), highlighting that the alteration of mitochondrial Ca 2+ uptake is crucial for the unresponsiveness of mesothelioma cells to apoptotic stimuli, and silencing MCU by RNAi or NaV (sodium orthovanadate) treatment to restore the Ca 2+ homeostasis and mesothelioma sensitivity to apoptotic stimuli [29,30,34,[40][41][42][43][44][45][46][47][48]58].…”