Targeting vacuolar H+-ATPases as a new strategy against cancer.
Growing evidence suggests a key role of tumor acidic microenvironment in cancer development, progression, and metastasis. As a consequence, the need for compounds that specifically target the mechanism(s) responsible for the low pH of tumors is increasing. Among the key regulators of the tumor acidic microenvironment, vacuolar H(+)-ATPases (V-ATPases) play an important role. These proteins cover a number of functions in a variety of normal as well as tumor cells, in which they pump ions across the membranes. We discuss here some recent results showing that a molecular inhibition of V-ATPases by small interfering RNA in vivo as well as a pharmacologic inhibition through proton pump inhibitors led to tumor cytotoxicity and marked inhibition of human tumor growth in xenograft models. These results propose V-ATPases as a key target for new strategies in cancer treatment.
Fais
Stefano
S
Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy. stefano.fais@iss.it
De Milito
Angelo
A
You
Haiyan
H
Qin
Wenxin
W
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007477:Ions / Q000737:chemistry; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism* / Q000628:therapy*; D006180:Proton-Translocating ATPases / Q000737:chemistry*; D017382:Reactive Oxygen Species; D014617:Vacuoles / Q000378:metabolism*
D000970:Antineoplastic Agents; D007477:Ions; D017382:Reactive Oxygen Species; D006180:Proton-Translocating ATPases