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Abstract
It is hypothesized that the restoration of the normal homeostatic, differentiated state of neoplastic cells involves the degradation of un-wanted proteins that contribute to the malignant behavior of the cell and/or the synthesis of proteins that define the functional characteristics of differentiated cells. This hypothesis can be used as the basis for developing newer anticancer agents that can induce malignant cell differentiation. One potentially useful compound is bryostatin 1.
Bryostatin 1 (bryo 1) is isolated from the marine bryozoan Bugula neritina and has been shown to be a protein kinase C activator and inducer of neoplastic cell differentiation. Bryo 1 decreased expression of Bcl-2 in a human pre-B ALL cell line, Reh through the ubiquitin-proteasome pathway. However, this decrease in Bcl-2 was insufficient in inducing apoptosis. Therefore, bryo 1's ability to modulate other regulators of apoptosis was investigated showing that bryo 1 treatment of the Reh cells induced cIAP-1 protein expression. Bryo 1 has also been shown to activate the nuclear transcription factor NF-κB which transactivates the inhibitor of apoptosis family members, cIAP-1, survivin and XIAP. In the Reh cell line, cIAP-1 is modulated through NF-κB transactivation while XIAP is degraded, through proteasome degradation and survivin is left unchanged.
Most recent studies showed that bryo 1 combined with the novel antitubulin inhibitors auristatin PE or dolastatin 10 resulted in downregulation of cIAP-1 protein and a dramatic increase in apoptosis which was not detected after bryo 1 or the antitubulin inhibitor treatment alone. These combinations also proved to increase the expression of the proapoptotic molecule Bax which is believed to, in combination with a decrease in Bcl-2, initiate a cysteine protease (caspase) cascade which ultimately ends in apoptotic cell death. Reh cells were also not induced to apoptose after treatment with the antitubulin agent vincristine alone. However, when Reh cells were treated sequentially with bryo 1 (24h) followed by vincristine for 24–72h, a significant increase in apoptosis was recorded which over time was lost, indicating an acquired resistance. We investigated this acquired resistance as a result of cIAP-1 induction, showing that cIAP-1 increases in the above combinations, in contrast to the decreased cIAP-1 and apoptosis increase recorded with the other antitubulin agents.
