Roles of Ion fluxes, metabolism and redox balance in cancer therapy.

Recent Advances: The 2019 Nobel Prize awarded to the mechanisms for oxygen sensing and adaptation according to oxygen availability, highlighting the fundamental importance of gaseous molecules. Gaseous molecules including reactive oxygen species (ROS) can interact with different cations generated during metabolic and redox dysregulation in cancer cells. Crosstalk between calcium signaling and metabolic/redox pathways leads to network-based dyregulation in cancer.

SIGNIFICANCE: Recent discovery on using small molecules targeting the ion channels, redox signaling, and protein modification on metabolic enzymes can effectively inhibit cancer growth. Several FDA-approved drugs and clinical trials are ongoing to target the calcium channels, such as TRPV6 and TRPM8. Multiple small molecules from natural products targets on metablic and redox enzymes to exert anti-cancer effect.

CRITICAL ISSUES: Small molecules targeting key ion channels, metabolic enzyme that control key aspects of metabolism and redox proteins are promising, but their action mechanisms of the target are needed to be elucidated with advanced -omic technologies which can give network-based and highly-dimensioal data. In addition, small molecules that can directly modify the protein residues has emerged as a novel anti-cancer strategy.

FUTURE DIRECTIONS: Advanced technology accelerates the detection of ions, metabolic, and redox changes in clinical samples for diagnosis and informs the decision of cancer treatment. The improvement of ROS detection, ROS target identification, and computational-aid drug discovery also improve clincal outcome.Overall, network-based or holistic regulation of cancer via ion therapy, metabolic and redox intervention are promising as new anti-cancer strategies.