Protein kinase C inhibitors as inducers of apoptosis for cancer therapy

The antitumour activity of many chemotherapeutic agents is a consequence of their induction of apoptosis. Apoptosis represents an active, energy dependent process in which the cell participates in its own destruction. Recent investigations into the elements that regulate apoptosis have provided evidence for the existence of a balance between pro- and anti-apoptotic signalling. This balance appears to be reciprocally regulated through the sphingomyelin signal transduction pathway that mediates the pro-apoptotic signals, and the activation of the phosphoinositide-protein kinase C (PKC) pathway that mediates the anti-apoptotic signals. Thus, inhibition of the phosphoinositide-PKC pathway by PKC specific inhibitors may be sufficient to tip the balance in favour of pro-apoptotic signals. Consequently, PKC presents a novel target for anti-cancer therapy. Members of the PKC family are characterised by a unique amino-terminal regulatory domain, which contains the phorbol ester binding site, and a carboxyl-terminal catalytic domain, which contains an ATP-binding site. The catalytic domain of PKC is highly homologous to the catalytic domain of other protein kinases. The development of a PKC inhibitor for clinical trials will ultimately depend on an agent that is either highly specific for the catalytic domain of PKC or inhibits PKC by interfering with its unique regulatory site. A series of PKC inhibitors are now in Phase I clinical trial as single agents. These drugs include safingol (regulatory), UCN-01 (catalytic), flavopiridol (catalytic), and bryostatin 1 (regulatory). These agents have been shown in a series of in vitro models to enhance significantly the induction of apoptosis by chemotherapy. Based on these observations, clinical trials will soon be initiated that combine these agents with chemotherapy, as a means of substantially increasing the chemotherapeutic effect.