Targ Oncol (2006) 1: 42–53 DOI 10.1007/s11523-005-0003-0 PERSPECTIVES A. Ghoul . M. Serova . K. A. Benhadji . E. Cvitkovic . S. Faivre . E. Philips . F. Calvo . F. Lokiec . E. Raymond Protein kinase C α and δ are members of a large kinase family of high potential for novel anticancer targeted therapy Published online: 11 January 2006 # Springer-Verlag 2006 Abstract Protein kinase C (PKC) family enzymes partic- ipate in several cell-signaling pathways by controlling proliferation, differentiation, senescence, invasion, and apoptosis both in normal and in cancer cells. The PKC family consists of serine/threonine kinases including 12 isoforms, which could be divided in three groups based on their interactions with calcium and diacylglycerol. Studies have suggested that PKCs play a role in carcinogenesis and maintenance of malignant phenotype. Potentiation of ma- lignant phenotype may be mediated by activation of selective PKC isoenzymes and/or through altered isoen- zyme expression profile compared to the originating tissue. PKC-δ is thought to mediate anticancer effects and PKC-α has often been linked to malignant phenotype. During the past few years, preclinical and clinical data with first generation PKC inhibitors/ activators provided insights that PKCs may indeed represent attractive targets for the discovery of small molecules with new anticancer proper- ties. This review focuses on current knowledge on reg- ulation of PKC-δ and PKC-α in cancer progression highlighting the potential role of those kinases as targets for anticancer therapeutics. Keywords Cancer . Protein kinase C . Apoptosis . Caspase-3 . Cellular signaling . Carcinogenesis Introduction Molecularly targeted therapies using either small mole- cules such a imatinib mesylate or monoclonal antibodies such as cetuximab, trastuzumab and bevacizumab have been successfully introduced to treat patients with various cancers including breast cancer, colon cancer, chronic myeloid leukemia and gastrointestinal stromal tumors [1– 3]. Those drugs were specifically designed to interact with key cellular proteins such as tyrosine kinase receptors associated with tumor development and progression. Interestingly, targeted therapeutics have shown a high degree of tumor specificity, often resulting in a safe toxicity profile when compared to chemotherapeutic agents. Targeted therapies were often shown not only to interact directly with critical function in cancer cells, but also to prevent endothelial cell proliferation and invasion [3–5], resulting in tumor growth inhibition by blocking angio- genesis [5, 6]. Intracellular serine/threonine kinases have been recently found to mediate the crossroad of multiple signaling pathways important for the downstream signal transduction of cellular proliferation and invasion following activation of receptor tyrosine kinases [7, 8]. Three major signaling pathways including the mitogen-activated protein kinase/ ras (MAPK), the phosphatidylinositol 3 kinase/AKT, and the protein kinase C (PKC) family signaling pathways [9] have been described to play an important role in cancer proliferation [10, 11] (Fig. 1). Drugs in development inhibiting such kinases at the convergence of multiple- signaling pathways may prove to be particularly useful as anticancer therapies in the future [12]. PKCs belong to a family of serine/threonine kinases and are cytosolic nucleotide-independent enzymes that phos- phorylate serine and threonine residues in many target proteins. The first members of this family were identified in 1977 in bovine cerebellum by Nishizuka and co-workers as A. Ghoul . M. Serova . K. A. Benhadji . E. Philips . F. Lokiec Department of Clinical Pharmacology, Centre René Huguenin, Saint-Cloud, France M. Serova . F. Calvo U716, Hôpital Saint-Louis, Paris, France E. Cvitkovic CAC Oncology, Le Kremlin Bicêtre, France A. Ghoul . S. Faivre . E. Raymond (*) Department of Medical Oncology Service Inter Hospitalier de Cancérologie (SIHC), Beaujon University Hospital, 100, Boulevard du Général Leclerc, 92118 Clichy Cedex, France e-mail: eric.raymond@bjn.aphp.fr Tel.: +33-1-40875617 Fax: +33-1-40875487