Clostridium perfringens enterotoxin (CPE) causes the symptoms associated with several common
gastrointestinal diseases. CPE is a 35 kDa
polypeptide consisting of three structured domains, that is, C-terminal domain I (responsible for receptor binding), domain II (responsible for oligomerization and membrane insertion), and domain III (which may participate in physical changes when the CPE
protein inserts into membranes). Native CPE binds to
claudin receptors, which are components of the tight junction. The bound toxin then assembles into a hexameric prepore on the membrane surface, prior to the insertion of this oligomer into membranes to form an active pore. The toxin is especially lethal for cells expressing large amounts of
claudin-3 or -4, which includes many
cancer cells. Initial studies suggest that native CPE has potential usefulness for treating several
cancers where
claudin CPE receptors are overexpressed. However, some challenges with immunogenicity, toxicity, and (possibly) the development of resistance may need to be overcome. An alternative approach now being explored is to utilize C-CPE, which corresponds approximately to receptor binding domain I, to enhance paracellular permeability and delivery of chemotherapeutic agents against
cancer cells. Alternatively, C-CPE fusion
proteins may prove superior to use of native CPE for
cancer treatment. Finally, C-CPE may have application for other medical treatments, including vaccination or increasing
drug absorption. The coming years should witness increasing exploitation of this otherwise formidable toxin.