T-Type Calcium Channels: A Potential Novel Target in Melanoma

Abstract

T-type calcium channels (TTCCs) are overexpressed in several cancers. In this review, we summarize the recent advances and new insights into TTCC biology, tumor progression, and prognosis biomarker and therapeutic potential in the melanoma field. We describe a novel correlation between the Cav3.1 isoform and the increased basal autophagy in BRAF V600E -mutant melanomas and after acquired resistance to BRAF inhibitors. Indeed, TTCC blockers reduce melanoma cell viability and migration/invasion in vitro and tumor growth in mice xenografts in both BRAF-inhibitor-sensitive and -resistant scenarios. These studies open a new, promising therapeutic approach for disseminated melanoma and improved treatment in BRAFi relapsed melanomas, but further validation and clinical trials are needed for it to become a real therapeutic option.

Antihypertensives and melanoma: An updated review

“…Voltage‐gated T‐type calcium channels have been found to be upregulated in various cancers, including melanoma (Das et al., 2012). T‐type calcium channels are unique in that they are the only low‐voltage calcium channels, and thus require minimal depolarization to open (Barcelo et al., 2020). Furthermore, these channels are not expressed in epithelial cells, making T‐type CCBs a potentially useful drug for the treatment of melanoma (Taylor et al., 2008).…”

“…Voltage-gated T-type calcium channels have been found to be upregulated in various cancers, including melanoma (Das et al, 2012). T-type calcium channels are unique in that they are the only low-voltage calcium channels, and thus require minimal depolarization to open(Barcelo et al, 2020).…”

Store-Independent Calcium Entry and Related Signaling Pathways in Breast Cancer

“…Some VGCC see their expression and activity being altered in BC. This is the case in T-type Ca 2+ channels, such as Cav3.1, Cav3.2, which are overexpressed in BC tissue [ 54 , 55 ]. Indeed, through an experimental and informatic study using microarray analysis, it has been found that certain L-type channels, such as Cav1.2 and Cav1.3, seem to be overexpressed in different types of cancer, including BC, and participate in inward Ca 2+ entry following melatonin and 5α-dihydrotestosterone perfusion [ 56 , 57 , 58 ].…”

Mibefradil alters intracellular calcium concentration by activation of phospholipase C and IP3 receptor function

“…Recently, mibefradil has seen a renewed pharmacological interest being an FDA "orphan drug" approved for its efficacy in cancer management [6][7][8]. Mibefradil has been used to treat ovarian and pancreatic cancer, glioblastoma and has an anti-proliferative effect on several cancer cell lines [8][9][10][11][12][13].…”

“…Recently, mibefradil has seen a renewed pharmacological interest being an FDA "orphan drug" approved for its efficacy in cancer management [6][7][8]. Mibefradil has been used to treat ovarian and pancreatic cancer, glioblastoma and has an anti-proliferative effect on several cancer cell lines [8][9][10][11][12][13]. In melanoma cells, the anti-proliferative and anti-tumoral properties of mibefradil were dependent on caspase activation, the transfer of Ca 2+ into the endoplasmic reticulum (ER) [14,15], and the inhibition of basal macroautophagy which is constitutively active in melanoma cells [16].…”