Na⁺/Ca²⁺ exchangers: Unexploited opportunities for cancer therapy?

Calcium is a well-studied ion that acts as a cofactor in several reactions and as intracellular second messenger. It plays crucial roles in living cells by regulating several processes from cell division to death. The disruption of Ca²⁺ homeostasis is related to cell and tissue damage and it is involved in several pathological conditions and diseases, including cancer. Tumor cells exhibit several molecular features in relation to normal cells in order to acquire proliferative and survival advantages, and Ca²⁺ signaling is directly or indirectly involved in these pathways. Thus, changes in the expression of Ca²⁺ channels and pumps are frequently described in some cancers, including transient receptor potential (TRP) family channels, store- and voltage-gated Ca²⁺ channels, store release channels, and Ca²⁺ ATPases. Although the sodium/calcium exchanger (Na⁺/Ca²⁺ exchanger; NCX) and the therapeutic potential of its inhibitors have been extensively studied in heart diseases, there are few studies about the molecular and functional aspects of NCX in cancer. Here, the current knowledge about NCX in cancer will be reviewed and possible strategies to target NCX for cancer therapy will be discussed.