Evaluation of sphinganine and sphingosine as human breast cancer chemotherapeutic and chemopreventive agents.
No comparative study of the effects of sphingolipid metabolites on proliferation and differentiation in normal human breast epithelial cells versus stem cells and tumorigenic cells has been reported. The purpose of this study was to evaluate the chemotherapeutic and chemopreventive potential of sphingoid bases (sphingosine and sphinganine) using a novel cell culture system of normal human breast epithelial cells (HBEC) developed from breast tissues of healthy women obtained during reduction mammoplasty (Type I HBEC with stem cell characteristics and Type II HBEC with basal epithelial cell phenotypes) and transformed tumorigenic Type I HBEC. The results show that sphinganine inhibited the growth and induced apoptosis of transformed tumorigenic Type I HBEC more potently than sphingosine (IC(50) for sphinganine 4 microM; sphingosine 6.4 microM). Both sphinganine and sphingosine at high concentrations (8-10 lM) arrested the cell cycle at G(2)/M. Sphinganine inhibited the growth and caused death of Type I HBEC more strongly than sphingosine. In comparison, Type II HBEC (normal differentiated cells) were less sensitive to the growth-inhibitory effects of sphingoid bases than Type I HBEC (stem cells) or transformed tumorigenic Type I HBEC, suggesting that sphingoid bases may serve as chemotherapeutic agents. At concentrations (0.05, 0.1, and 0.5 microM) that are below the growth-inhibitory range, sphingoid bases induced differentiation of Type I HBEC to Type II HBEC, as detected morphologically and via expression of a tumor suppressor protein, maspin, which is a marker of Type II HBEC. Thus, sphingoid bases may function as chemotherapeutic as well as chemopreventive agents by preferentially inhibiting cancer cells and eliminating stem cells from which most breast cancer cells arise.
Ahn
Eun Hyun
EH
University of Pennsylvania School of Medicine, Department of Pathology and Laboratory Medicine, 506 Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA. ahneun@gmail.com
Chang
Chia-Cheng
CC
Schroeder
Joseph J
JJ
D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control; D002453:Cell Cycle / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D014411:Neoplastic Stem Cells; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D013110:Sphingosine; C005682:safingol