The effects of bryostatin on the grwoth of salivary gland tumor cells and the replication of herpes simplex virus

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The effects of protein kinase activators, bryostation and 12-o-tetradecanoyl phorbol-13-acetate(TPA) on herpes simplex virus type 1 (HSV-1) infection was examined. Bryostatin and TPA enhanced the cytopathic effect of fusion-inducing HSV-1 in mouse submandibular gland carcinoma cells (c112) and A431 epidermoid carcinoma cells. The virus yield was also increased if infection was initiated at a low multiplicity of infection. Rhodamine-phalloidin staining of actin filament revealed that bryostatin and TPA decreased cortical actin fiber and intercellular connection, and stimulated the development of filopodia and long processes in mock-and HSV- 1 -infected cells. Rearrangement of actin filament was not observed by phorbol didecanoate which does not activate PKC.Actin disrupting drug cytochalasin D inhibited the enhancing effects of bryostaitin and TPA on cell fusion and virus production. Transfectin of PKC beta I gene produced cells which were more sensitive to the effect of TPA.In the PKC … More beta I-transfected cells which were pretreated with TPA and PKC inhibitor, H-7 or sphingosine simultaneously, the enhancing effects of TPA on polykaryocyte formation and actin filament was reduced. These findings indicate that TPA enhances the cytopathic effect of HSV-1 in a PKC dependent manner, and that actin filament reorganization is associated with this enhancing effect of TPA.Bryostatin and TPA reduced the growth potential of c112 cells and A431 cells at the concentrations of 10 and 100 nM.When theses cells were treated with PKC activator and differentiation agent hexamethylene bisacetamide simultaneously, apoptosis was induced at 24 h later, indicating that PKC activator can act as a potent anti-cancer drug. In this regard, bryostatin which does not promote tumor induction seems to be the candidate as an anti-cancer drug. However, bryostatin also promotes HSV-1 infection. Thus, when patients are treated with PKC activators, careful attention is required against the occurrence of recurrence and aggravation of HSV-1 infection. Less