The role of the phorbol ester receptor/protein kinase C in the sensitivity of leukemic cells to anthracyclines.
The phorbol ester receptor (PER), which is believed to be identical to protein kinase C (PKC), has been implicated in the control of the sensitivities of tumor cells to certain forms of cancer chemotherapy. We evaluated the effects of regulating the expression of PER/PKC on the sensitivity of the R1B6 subclone of HL-60 human promyelocytic leukemic cells to anthracyclines. This cell line is resistant to the effects of phorbol esters on cellular differentiation by virtue of a down-regulated PER. R1B6 cells were maintained in phorbol 12, 13 dibutyric acid (PDBu). Twenty four to thirty six hours after removal of PDBu from the medium there was a 3-fold increase in the number of receptors compared to baseline values measured by [3H]-PDBu binding and a marked increase in the activity of PKC as measured by calcium-phospholipid dependent incorporation of [32P] into histone. Despite these changes in the number of PER and in the activity of PKC there was no difference in the cellular accumulation of [3H]-daunomycin or in the sensitivity of cells to the toxic effects of doxorubicin. Furthermore, there was no difference between the R1B6 cells and the parental HL-60 line in their intrinsic sensitivities to doxorubicin. These studies demonstrate that alterations in the expression of PER and the activity of PKC alone are not sufficient to influence anthracycline accumulation or toxicity in R1B6 human leukemic cells in contrast to recently reported results using other cell lines.
Hait
W N
WN
Department of Medicine, Yale University School of Medicine, New Haven, CT 06510.
DeRosa
W T
WT
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D066298:In Vitro Techniques; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D015240:Phorbol 12,13-Dibutyrate / Q000493:pharmacokinetics; D011493:Protein Kinase C / Q000096:biosynthesis / Q000502:physiology*; D011955:Receptors, Drug / Q000096:biosynthesis / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000903:Antibiotics, Antineoplastic; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D011955:Receptors, Drug; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D003630:Daunorubicin