Protein kinase C delta (PKC delta) inhibitors as a target for pro-apoptotic treatment of cancer

Colorectal cancer is the third leading cause of cancer-related deaths in the United States with approximately 130,000 new cases diagnosed per year. Despite advances in surgical management and multimodality therapy (click here for an analysis of colon cancer therapeutics), approximately 50% of patients with cancers of the colon and rectum die from their disease. A significant obstacle for the successful management of patients with colorectal cancer is intrinsic drug resistance or, in patients who initially respond to chemotherapy, acquired drug resistance.

Apoptosis stimulators have emerged as key targets for the control of cancer. Over the past few years targeting the endogenous inhibitors of apoptosis such as Bcl-2 (see the Focus on Oncology section of this edition of TherapeuticUpdates) and the IAP ("Inhibitor of Apoptosis Proteins") family of proteins has emerged as an important strategy for modulating apoptosis (see our recent analysis of this field). This field has grown exponentially since 1995 and continues to do so.

IAPs bind and potently inhibit the proteolytic activities of the pro-apoptotic caspases 3, 6 and 7, block activation of pro-caspase-9, and have been implicated in many different types of cancer including those with the highest mortality rates. Although XIAP and survivin remain the better known members of the IAP family, 8 human IAPs have now been identified. In colorectal cancer survivin was significantly related to a dramatically increased disease-free survival rate and to a reduced risk for distant metastases. Furthermore a convincing body of data has linked the IAPs to the resistance of cancer cells to radiation and chemotherapeutic intervention. For example, low dose gamma-irradiation increases the expression of XIAP in non-small cell lung carcinoma cells evoking resistance to radiation-induced apoptosis. On the other hand IAP antisense oligonucleotides have been shown to increase the sensitivity of cancer cells to irradiation. Hence the blockade of IAP expression or function offers a powerful tool for the treatment of cancer.

In a recent study, Mark Evers’ group at The University of Texas Medical Branch has focused on the IAP, cIAP2, and particularly its modulation by the PKC family. The various isoforms of PKC are involved in a variety of cellular processes involved in tumor progression. Inhibition of the delta isoform of PKC increases apoptosis. In their JBC paper, Wang et al report that PMA, which stimulates PKC increases the expression of cIAP2 in Caco-2 colon cancer cells while the expression of other IAPs was largely unaffected. This phenomenon was related to an increase in PKC delta activity and indeed blocking this enzyme prevented PMA from increasing cIAP2 expression. PMA-induced cIAP2 expression appears to be a general feature of colon cancer cells and furthermore this phenomenon was mediated by NF-kappaB, which itself can be activation by PKC delta.

This study clearly delineates a survival pathway involving the activation of NF-kappaB and overexpression of cIAP in response to the stimulation of PKC delta. While previous studies have successfully employed antisense oligonucleotides raised against IAPs to reestablish sensitivity to apoptotic signals in cancer cells, this study suggests that small molecule inhibitors of PKC delta may be of similar value in the treatment of colorectal cancer. This lends support to the concept of developing PKC delta inhibitors. Interested parties may wish to visit the November edition of "Licensing Opportunities" which lead compounds that can inhibit protein kinase C isoforms.

Entry date Monday, November 17, 2003

Adapted from Wang et al, J Biol Chem. 2003 Oct 3