T-type Ca2+ Channels: T for Targetable

Abstract

In the last decade TTCC have been unveiled as key regulators of cancer cells biology and thus have been proposed as chemotherapeutic targets. Indeed in vitro and in vivo studies indicate that TTCC pharmacological 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 Consequently mibefradil, a TTCC blocker approved in 1997 as an antihypertensive agent but withdrawn in 1998 because of drug-drug interactions, was granted 10 years later the orphan drug status by the FDA to investigate its efficacy against brain, ovary and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 physiological roles, together with the lack of selective pharmacological agents, has hindered a conclusive chemotherapeutic evaluation. Here we review the available evidence on TTCC expression, value as prognostic markers and effectiveness of their pharmacological blockade on cancer cells in vitro 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 TTCC as biomarkers or targetable molecules in cancer.