Between 1970 and 1994, cancer claimed the lives of about 0.5 million Americans every year. Incidence and mortality rates remain high today and the development of therapeutic strategies for the prevention and treatment of cancer thus represents a key priority for the pharmaceutical industry.

Although they have been linked to the carcinogenesis process for over 30 years, gap junctions have only recently emerged as a target for the treatment of cancer. During normal differentiation stem cells gradually start to express gap junction intercellular communication (GJIC) in what have been termed transit cells (partially differentiated stem cells). During the initiation stage of carcinogenesis, mutagenic changes such as the loss of telomorase activity, lead to a block in the differentiation of stem cells into transit cells or transit cells into differentiated cells. At this early stage of carcinogenesis however, tumor growth is prevented either in transit cells by contact inhibition by GJIC, or in stem cells through the effects of negative growth suppressors. During the promotion phase of carcinogenesis it is proposed that either one of these control processes are blocked leading to clonal expansion of cells devoid of GJIC. As promotion proceeds it has been suggested that further genetic changes occur such that growth eventually becomes promotor-independent and as a result benign lesions develop into malignant cancers.

The loss of GJIC in transit cells occurs as a result of oncogene activation, or the activity of carcinogens and growth factors. A number of mechanisms are responsible for the loss of GJIC: transcriptional down-regulation of connexins, post-translational modification of GJIC by activated oncogenes or by carcinogens, or defects in cell adhesion. Whatever the cause, loss of GJIC results in the inability of cells to receive apoptotic, growth suppressing or differentiation signals from their neighbors. Reintroducing GJIC into these cells facilitates growth control suggesting that GJIC proteins such as the connexins represent a therapeutic target.

The connexin family is comprised of a large number of proteins that are expressed in a cell specific fashion. For example Cx43 is expressed by epithelial but not hepatic cells, which express Cx32. Thus the carcinogen TPA is able to inhibit Cx43 but not Cx32 and therefore does not promote hepatic cancer suggesting that targeting connexins may allow for a highly type-specific approach to cancer.

The connexins offer hope for both chemotherapeutic and chemopreventative strategies. With regards to chemotherapy, reestablishing cell:cell communication is able to introduce a certain amount of homogeneity into an otherwise heterogeneous tumor environment. For example only a small proportion of molecules may be targeted by antibody delivered toxins or by chemotherapeutics however reintroduction of GJIC allows the spread of these molecules to adjacent cells allowing improve efficacy through the “bystander effect”. On the other hand the efficacy of cancer therapeutics is often limited by cell survival factors and endogenous inhibitors of apoptosis. GJIC may allow the buffering of these factors thereby increasing the susceptibility of cancer cells to cell death. Reestablishing connexin activity or expression may therefore serve as a powerful adjunct to various other anti-cancer treatments.

On the other hand, connexins may be related to chemopreventative treatments. A wide variety of chemopreventative treatments such as the retinoids are known to increase GJIC. This suggests that the rational design of chemotherapeutics that specifically target GJIC may offer improved anticancer activity. On the other hand those molecules that reduce GJIC are likely to have tumor promoting activity and this should be considered in toxicity evaluation. One recent example of this has been highlighted by field-leading researchers at Michigan State University who have reported that cannabinoids inhibit GJIC at noncytotoxic doses and furthermore they also activated ERK1 and ERK2, powerful mitogenic signals. The cannabinoids may therefore not only lead to tumor promotion by their effects on GJIC but they may also enhance cell proliferation increasing the chances of malignancy developing.

In summary therefore, therapeutic agents that interfere with GJIC should be treated with caution while those that reintroduce or reactivate connexins may represent powerful therapeutic tools. Very few molecules that specifically target gap junction have been developed and this therefore represents a major field of future drug development activity.

Entry date February, 2003

Adapted from Upham et al, 2003 Int J Cancer 2003 Mar 10;104(1):12-18 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk