Modulating protein kinase C (PKC) to increase the efficacy of chemotherapy: stepping into darkness.
The identification of molecules that promote chemotherapeutic resistance would allow rationally designed approaches to abrogate this resistance, thereby possibly improving clinical outcomes for patients with cancer. In this regard, the PKC family is attractive for targeting, because it is comprised of a family of isoforms that play key roles in multiple cellular processes and can contribute to cellular transformation. Encouraging in vitro data originally showed that approaches to modulate PKC activity through small-molecule inhibitors or genetic manipulation could affect tumor cell survival. Recently, some of these approaches have begun clinical testing. Early-stage clinical trials revealed scattered clinical responses to these agents, but the most recent clinical trials have shown that combining modulators of PKC with standard chemotherapy does not improve outcome over chemotherapy alone. In this review, we will trace the development of these approaches, and discuss possible explanations for the recent negative results. Importantly, we will suggest guidelines for the clinical evaluation of PKC modulators.
Lorenzo
Patricia S
PS
Natural Products Program, Cancer Research Center of Hawaii, Honolulu, HI 96813, USA.
Dennis
Phillip A
PA
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011493:Protein Kinase C / Q000096:biosynthesis*; D016896:Treatment Outcome
D011493:Protein Kinase C