Submitted to: Carcinogenesis
Publication Type: Peer reviewed journal
Publication Acceptance Date: 12/21/2007
Publication Date: 2/28/2008
Publication URL: http://handle.nal.usda.gov/10113/19366
Citation: Li, G., Lee, H., Wang, Z., Hu, H., Liao, D.J., Watts, J.J., Combs, G.F., Lu, J. 2008. Superior In Vivo Inhibitory Efficacy of Methylseleninic Acid Against Human Prostate Cancer over Selenomethionine or Selenite. Carcinogenesis. 29(5):1005-1012. Interpretive Summary: We undertook to determine the efficacy against prostate cancer cells of methylselenol which has been implicated as an active anti-cancer selenium (Se) metabolite. We did this by evaluating the abilities of two compounds that appear to be metabolized to methylselenol, methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC), comparing each with two food forms of Se, selenomethionine (SeMet) and selenite for their abilities to inhibit the growth of human prostate cancer xenografts in athymic nude mice. We administered each Se-compound daily by a single oral dose starting the day after inoculating the mice by injecting the cancer cells subcutaneously. We found that both methylselenol precursors inhibited xenograft growth, and were more potent in doing so than either SeMet and selenite, even though SeMet lead to greater accumulation of Se in both tumor and normal tissue. Unlike the other Se-compounds, selenite was genotoxic, as indicated by increased DNA damage in the peripheral lymphocytes. We conclude that metabolic precursors of methylselenol can inhibit human prostate cancer without being genotoxic.
Technical Abstract: Background: Methylselenol has been implicated as an active anti-cancer selenium metabolite. Its in vivo efficacy for prostate cancer has yet to be established. Methods: We evaluated the in vivo growth inhibitory effects of two presumed methylselenol precursors methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in comparison with selenomethionine (SeMet) and selenite in DU145 and PC-3 human prostate cancer xenografts in athymic nude mice. Each selenium compound was given by a daily single oral dose regimen starting the day after the subcutaneous inoculation of cancer cells. We analyzed selected biomarkers including serum and tissue selenium content, apoptosis indices, tumor microvessel density and DNA single strand breaks to explore possible mechanisms. Results: MSeA and MSeC exerted a dose-dependent inhibition of DU145 xenograft growth and both were more potent than SeMet and selenite, in spite of less tumor and liver selenium retention than in the SeMet-treated mice. Only selenite treatment increased DNA single strand breaks in the peripheral lymphocytes, indicating systemic genotoxicity. Biomarker profiling suggested that MSeA affected tumor microvessel density (angiogenesis) more than MSeC, whereas MSeC increased TUNEL and cleaved caspase-3 indices (apoptosis) more than MSeA. In the PC-3 xenograft model, only MSeA was growth inhibitory at a dose of 3 mg/kg body weight. Conclusions: Our data demonstrated superior in vivo growth inhibitory efficacy of MSeA against human prostate cancer over SeMet and selenite, and suggested possible differential molecular and cellular targets for MSeA versus MSeC to mediate their inhibitory efficacy, in addition to their purported common methylselenol metabolite.