Equivalent death of P-glycoprotein expressing and nonexpressing cells induced by the protein kinase C inhibitor staurosporine.
P-glycoprotein (P-gp) is an ATP-dependent drug pump that confers multidrug resistance. In addition to its ability to efflux toxins P-gp can also inhibit apoptosis induced by a wide array of cell death stimuli that rely on activation of intracellular caspases for full function. We have previously demonstrated that stimuli including drugs such as hexamethylene bisacetamide (HMBA), the cytotoxic lymphocyte granule protein granzyme B, and pore-forming proteins such as perforin, kill P-gp positive cells in a caspase-independent manner. We therefore hypothesised that drugs that are not effluxed by P-gp and which induce cell death in the absence of caspase activation could induce death of P-gp expressing cells. Staurosporine has been previously shown to kill cells in the absence of caspase activation. Consistent with our hypothesis, we demonstrate here that staurosporine can equivalently kill P-gp(+ve) and P-gp(-ve) tumor cell lines in a caspase-independent manner.
Tainton
K M
KM
The Peter MacCallum Cancer Institute, Saint Andrews Place, East Melbourne 3002, Victoria, Australia.
Ruefli
A A
AA
Smyth
M J
MJ
Johnstone
R W
RW
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004791:Enzyme Inhibitors; D011493:Protein Kinase C; D019311:Staurosporine