bryostatin-1 and Edema

The present study was designed to investigate the tumor inhibitory potential of bryostatin 1 in a 12‑O‑tetradecanoylphorbol‑13‑acetate (TPA)‑induced mouse model of skin cancer. The radical inhibition potential of various doses of bryostatin 1 was investigated against 2,2‑diphenyl‑1‑picrylhydrazyl (DPPH) bleach in vitro. The DPPH radical potential was observed compared with treatment with 5, 10, 15, 20, 25 and 30 µM doses of bryostatin 1. In vivo, bryostatin 1 prevented the TPA‑mediated increase in the level of H2O2 and myeloperoxidase in mouse epidermal tissue. Pretreatment of the mice with bryostatin 1 (30 µM) followed by administration of TPA reduced the edema, as demonstrated via punched‑out mouse ear tissue, to 7.2 mg, compared with 14 mg in the TPA‑treated group. Treatment with bryostatin 1 prior to TPA administration markedly prevented the inflammation of the skin by inhibiting hyperplasia in the epidermal layer and the aggregation of inflammatory cells. The results demonstrated that treatment of mice with bryostatin 1 at a 30 µM dose prior to TPA administration significantly (P<0.005) inhibited the TPA‑mediated increase in the level of COX‑2. The activity of ornithine decarboxylase, increased by TPA, was additionally inhibited following pretreatment of the mice with bryostatin 1. In the mice treated with bryostatin 1 at 30 µM doses prior to the administration of TPA, the appearance of papillomas was 20%, compared with 100% in the TPA group. Mice pretreated with bryostatin 1 at 30 µM doses prior to TPA administration exhibited the appearance of 0.4 mean papillomas in each animal, compared with 5.2 in the TPA group. Therefore, the results of the present study demonstrated that bryostatin 1 inhibited the development and progression of tumors of skin in the mice, through the prevention of inflammation‑inducing processes and the quenching of radicals. Therefore, bryostatin 1 maybe considered to be adrug of importance in the treatment of skin tumor.

Topics: Animals; Antineoplastic Agents; Bryostatins; Cyclooxygenase 2; Disease Models, Animal; Edema; Female; Mice; Ornithine Decarboxylase; Peroxidase; Skin Neoplasms; Tetradecanoylphorbol Acetate

The tumor promoters 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a strong activator of protein kinase C (PKC) and okadaic acid, which is ineffective in this respect, induce a rapidly developing ('early') edema of the mouse ear. Bryostatin, another potent activator of PKC, is unable to induce an 'early' edema but causes a more delayed development of edema at a time when most of the PKC is down-regulated. The PKC inhibitor staurosporine neither inhibits the early TPA- nor the late bryostatin-induced edema, but suppresses the okadaic acid-induced edema very effectively. TPA as well as bryostatin, but not okadaic acid cause a down-regulation of PKC, which is not inhibited by staurosporine. The calmodulin antagonist cyclosporine A, which does not suppress PKC activity, very effectively inhibits the TPA-induced edema and down regulation of PKC. Hence we conclude that protein phosphorylation catalyzed by staurosporine-suppressable PKC is not involved in the induction of edema and PKC down-regulation by TPA but that a calmodulin dependent process may play a critical role in these and other TPA effects in mouse skin.

Topics: Alkaloids; Animals; Bryostatins; Cyclosporine; Edema; Ethers, Cyclic; Female; Lactones; Macrolides; Mice; Okadaic Acid; Protein Kinase C; Skin; Staurosporine; Tetradecanoylphorbol Acetate