Prospects for targeting protein kinase C isozymes in the therapy of drug-resistant cancer--an evolving story.
The seminal discovery in 1988 that selective protein kinase C (PKC) activators induce multidrug resistance (MDR) in human cancer cells spawned several years of intensive investigations; these studies were primarily directed at the question of whether isozyme-selective PKC antagonism could reverse MDR phenotypes produced in cancer cells by P-glycoprotein and other ATP-binding cassette (ABC) transporters. The first section of this commentary provides a succinct overview of those studies. In the second section, we evaluate why the enthusiasm for studies of the involvement of PKC in transport-related drug resistance is currently diminished, and we offer an assessment of whether the PKC/MDR field should be revisited. The final section of the commentary highlights recent developments in studies of PKC targeting in experimental cancer therapeutics, which continues to be a vibrant field. Highlights include the sensitization of cancer cells to radiation- and drug-induced apoptosis by PKC inhibition.
O'Brian
C A
CA
Department of Cancer Biology, UT M.D. Anderson Cancer Center, Houston, TX 77030, USA. obrian@mdacc.tmc.edu
Ward
N E
NE
Stewart
J R
JR
Chu
F
F
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes; D009369:Neoplasms / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011493:Protein Kinase C