Modulation of protein kinase C in antitumor treatment.
PKC isoenzymes were found to be involved in proliferation, antitumor drug resistance and apoptosis. Therefore, it has been tried to exploit PKC as a target for antitumor treatment. PKC alpha activity was found to be elevated, for example, in breast cancers and malignant gliomas, whereas it seems to be underexpressed in many colon cancers. So it can be expected that inhibition of PKC activity will not show similar antitumor activity in all tumors. In some tumors it seems to be essential to inhibit PKC to reduce growth. However, for inhibition of tumor proliferation it may be an advantage to induce apoptosis. In this case an activation of PKC delta should be achieved. The situation is complicated by the facts that bryostatin leads to the activation of PKC and later to a downmodulation and that the PKC inhibitors available to date are not specific for one PKC isoenzyme. For these reasons, PKC modulation led to many contradicting results. Despite these problems, PKC modulators such as miltefosine, bryostatin, safingol, CGP41251 and UCN-01 are used in the clinic or are in clinical evaluation. The question is whether PKC is the major or the only target of these compounds, because they also interfere with other targets. PKC may also be involved in apoptosis. Oncogenes and growth factors can induce cell proliferation and cell survival, however, they can also induce apoptosis, depending on the cell type or conditions in which the cells or grown. PKC participates in these signalling pathways and cross-talks. Induction of apoptosis is also dependent on many additional factors, such as p53, bcl-2, mdm2, etc. Therefore, there are also many contradicting results on PKC modulation of apoptosis. Similar controversial data have been reported about MDR1-mediated multidrug resistance. At present it seems that PKC inhibition alone without direct interaction with PGP will not lead to successful reversal of PGP-mediated drug efflux. One possibility to improve chemotherapy would be to combine established antitumor drugs with modulators of PKC. However, here also very contrasting results were obtained. Many indicate that inhibition, others, that activation of PKC enhances the antiproliferative activity of anticancer drugs. The problem is that the exact functions of the different PKC isoenzymes are not clear at present. So further investigations into the role of PKC isoenzymes in the complex and interacting signalling pathways are essential. It is a major challenge in the future to reveal whether modulation of PKC can be used for the improvement of cancer therapy.
Hofmann
J
J
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, A-6020 Innsbruck, Austria.
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018432:Drug Resistance, Multiple; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011493:Protein Kinase C