Use ofClostridium perfringensEnterotoxin and the Enterotoxin Receptor-Binding Domain (C-CPE) for Cancer Treatment: Opportunities and Challenges

Abstract

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.

Clostridium perfringens Type A Enterotoxin Damages the Rabbit Colon

“…This enterotoxin, which is an ϳ35-kDa single polypeptide with a unique amino acid sequence (5), belongs structurally to the aerolysin family of pore-forming toxins (6,7). CPE action begins with its binding to receptors, which include certain members of the claudin protein family (8)(9)(10). Claudins are ϳ20-to 27-kDa protein components of the mammalian tight junctions in epithelia and endothelia, where they serve important structural and functional roles (11).…”

Cysteine-Scanning Mutagenesis Supports the Importance of Clostridium perfringens Enterotoxin Amino Acids 80 to 106 for Membrane Insertion and Pore Formation

“…Known CPE receptors include certain members of the claudin family of tight junction proteins (7,8,18,25,36). Binding of the toxin to claudins initially results in formation of an SDS-sensitive, small (ϳ90-kDa) complex (38).…”

Development of an Anti–Claudin-3 and -4 Bispecific Monoclonal Antibody for Cancer Diagnosis and Therapy

“…CLDN-3 and -4 are receptors for CPE, but CPE also binds to CLDN-6, -7, -8, and -14 (Fujita et al, 2000). Although CPE-and C-CPE-based cancer therapy has established the proof of concept for CLDN-targeted cancer treatment, therapeutic interventions have been limited because of CLDN-member specificity and immunogenicity (Gao and McClane, 2012). Clone 5A5 showed binding specificity to CLDN-3 and -4.…”

“…C-CPE also enhanced sensitivity to chemotherapy in ovarian cancers by modulating the TJ integrity in mice xenograft models of human cancer (Gao et al, 2011). Thus, CPE and C-CPE have contributed to the proof of concept for CLDN-3-and -4-targeted cancer diagnosis and therapy (Gao and McClane, 2012). However, CPE and C-CPE also bind to CLDN-6, -7, -8, and -14 (Fujita et al, 2000), and are immunogenic (Sugii, 1994;Suzuki et al, 2011).…”