Inhibition of skin carcinomas but not papillomas by sphingosine, N-methylsphingosine, and N-acetylsphingosine

The sphingoid base backbones of sphingolipids are highly bioactive compounds that affect cell growth, differentiation, diverse cell behaviors, and programmed cell death. Therefore, the efficacy of sphingosine (SPH) and the analogs N-acetylsphingosine (NAS), N-methylsphingosine (NMS), octylamine (OCT), and sterylamine (STR) in the prevention of skin cancer was assessed in female Sencar mice by measuring effects on the induction of epidermal ornithine decarboxylase (ODC) activity and hyperplasia by 12-O-tetradecanoylphorbol-13-acetate (TPA) and effects on the induction of skin tumors by 7,12-dimethylbenz[a]anthracene (DMBA) and TPA. ODC was measured in the shaved dorsal skin of mice treated topically with 0.05-20 mu mol of these compounds 30 minutes before application of 8.5 nmol of TPA in 0.2 mi of acetone. ODC activity was inhibited by greater than or equal to 5 mu mol of SPH and STR, greater than or equal to 10 mu mol of NAS and NMS, and 20 mu mol of OCT. In contrast the induction of hyperplasia was not inhibited by application of these compounds 30 minutes before TPA. Two carcinogenesis studies were conducted with 10 nmol of DMBA as the initiator and 3.2 nmol of TPA (2x/wk for 15 wk) as the promoter. In the first study, NAS, NMS, OCT, and STR (0.05 and 0.5 mu mol) were applied before each TPA application. Papilloma incidence and multiplicity were not inhibited, but NAS (0.05 mu mol) and NMS (0.05 and 0.50 mu mol) increased cancer-free survival. In the second experiment, SPH, NAS, and NMS (0.05 and 0.5 mu mol) were applied 30 minutes before each TPA treatment and twice weekly for IO weeks after the final TPA treatment. Papilloma incidence and multiplicity were not inhibited; however, the proportion of mice without carcinoma was increased by both doses of SPH and by 0.5 mu mol of NAS. Thus low doses of sphingolipids that were not effective in inhibiting ODC activity, reducing hyperplasia, or preventing epidermal papilloma development were, nonetheless, effective in inhibiting carcinoma development.