BAX expression is associated with enhanced intracellular accumulation of paclitaxel: a novel role for BAX during chemotherapy-induced cell death.
SW626 cells that overexpress BAX are sensitized to the cytotoxic effects of paclitaxel and vincristine. It has been assumed that BAX mediates these effects through its ability to alter mitochondrial function, specifically by promoting the release of cytochrome c and facilitating the mitochondrial permeability transition. However, we have found that several early paclitaxel-mediated events are enhanced in SW626 transfectants that overexpress BAX, including G2-M-phase arrest, tubulin polymerization, and BCL-2 phosphorylation. We now demonstrate that these seemingly disparate effects are explained by an enhanced accumulation of paclitaxel in BAX-overexpressing cells, an effect due to diminished drug efflux. In contrast, drug efflux is increased in cells that do not overexpress BAX, resulting in low intracellular paclitaxel levels and relative resistance to the effects of this drug. Drug efflux in SW626 cells is mediated by a verapamil-inhibitable, non-MDR-1, non-MRP-1 transporter whose function or expression may be inhibited by BAX. These data suggest that stable transfectants that overexpress BAX may be sensitized to apoptotic cell death through a novel mechanism involving the enhancement of intracellular levels of naturally occurring toxins such as alkaloid derivatives.
Strobel
T
T
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Kraeft
S K
SK
Chen
L B
LB
Cannistra
S A
SA
D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D017209:Apoptosis / Q000187:drug effects*; D005260:Female; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D014162:Transfection; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000493:pharmacokinetics; D051028:bcl-2-Associated X Protein
D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014700:Verapamil; D014747:Vinblastine; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human