Model of bryostatin 1/paclitaxel interactions.
Acute exposure of leukemic cells to bryostatin 1 stimulates TNF-α production through a PKC-dependent mechanism and, in so doing, engages the extrinsic apoptotic pathway. However, activation of caspase-8 through this mechanism is insufficient, by itself, to trigger cell death. When leukemic cells are exposed to paclitaxel, mitochondrial dysfunction and cytochrome c release occur, resulting in a limited degree of caspase activation and cell death. The latter events are strikingly amplified by bryostatin 1–mediated activation of the extrinsic pathway. Finally, paclitaxel-mediated arrest of cells in G2M, where they are more sensitive to TNF-α–related lethality, contributes to the marked potentiation of cell death.
