Bryostatin 1 induces differentiation of B-chronic lymphocytic leukemia cells

Abstract

Peripheral blood cells from nine patients with B-chronic lymphocytic leukemia (B-CLL) were treated in vitro with bryostatin 1 (a macrocyclic lactone derived from a marine invertebrate). Like the phorbol ester 12- 0-tetradecanoyl-phorbol 13-acetate (TPA), bryostatin 1 activates protein kinase C (PKC), which plays a central role in the phosphatidylinositol signal transduction pathway. The effects of bryostatin 1 alone and in combination with TPA or with the calcium mobilizing ionophore A23187 were assessed by morphological appearance, cell adherence and aggregation, RNA and DNA synthesis, and immunoglobulin (Ig) production. While eight of nine B-CLL cultures remained proliferatively inert, bryostatin 1 could effectively trigger activation and differentiation of B-CLL cells in all cases as inferred by the induction of morphological changes, RNA synthesis, and monotypic Ig production. Addition of calcium ionophore A23187 to bryostatin 1- exposed cells resulted in significantly increased values for RNA synthesis and Ig production and in the acquisition of plasmacytoid morphology. Bryostatin 1 and the dual signal of bryostatin 1 plus A23187 mimicked the stimulatory action of TPA and the combination of TPA plus A23187, respectively. Overall, bryostatin 1 was less active than equivalent concentrations of TPA. This lesser efficacy may, however, reflect a quantitative rather than qualitative difference. Bryostatin 1 partially antagonized TPA-mediated effects on B-CLL cells suggesting different modes of action by the two activators. These studies indicate that bryostatin 1 has effective differentiation- inducing properties on B-CLL cells that can differentiation-inducing properties on B-CLL cells that can be accentuated by a calcium ionophore.

Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence

“…We demonstrate that CAR functionality can be indirectly improved via Bryostatin1-mediated increase in CD22 expression. However, Bryostatin1 has been previously implicated in directly affecting T-cell function (25,26). Although Bryostatin1 attenuated IFNg production by CD22 CART, Granzyme B production was increased and there was ultimately no adverse effect on in vitro or in vivo cytotoxicity.…”

“…Bryostatin1 modulates PKC isoforms which play an important role in T-cell receptor signaling pathways (25,26). With Figure 2.…”

Protein kinase C in cellular transformation: a valid target for therapy?

“…Initial studies assessing the role of PKC in CLL cells utilized reagents such as the macrocyclic lactone bryostatin and the phorbol ester PMA, which globally modulate PKC activities and signalling pathways. In this way, elevated PKC activity was shown to play a role in CLL cell differentiation [ 27 , 28 ], enhanced CLL immunomodulation [ 29 ] and increased cell survival and chemoresistance [ 30 , 31 ]. The role of PKC in these processes was inferred by the use of PKC selective inhibitors; however, these studies did not establish the function of individual PKC isoforms.…”

Elucidating the role of protein kinase C in chronic lymphocytic leukaemia

“…In addition, TPA treatment results in a decrease in chemotherapy-induced apoptosis in CLL cells, preventing both dexamethasone-and fludarabine-induced apoptosis [21,23]. Similarly, Bryostatin-1 has been shown to induce CLL differentiation towards a CD11c hairy celllike phenotype both in vitro and in a Phase II clinical trial [24][25][26]. Additionally, Bryostatin-1 treatment prevented fludarabine-and dexamethasone-induced apoptosis of CLL cells through a mechanism involving the upregulation of the anti-apoptotic factor Mcl-1 and the caspase inhibiting IAP family member, X-linked IAP (XIAP), thus correlating with enhanced cell survival [27].…”