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ORIGINAL RESEARCH ARTICLE

Evaluation of Sphinganine and Sphingosine as Human Breast Cancer Chemotherapeutic and Chemopreventive Agents

Eun Hyun Ahn^*,1,2, Chia-Cheng Chang^, and Joseph J. Schroeder^*,3

^* Departments of Food Science and Human Nutrition; Pediatrics and Human Development; and National Food Safety and Toxicology Center, Michigan State University, East Lansing, Michigan 48824

To whom requests for reprints should be addressed at ¹ University of Pennsylvania School of Medicine, Department of Pathology and Laboratory Medicine, 506 Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104. E-mail: ahneun{at}gmail.com or ahne{at}mail.med.upenn.edu

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 (IC₅₀ for sphinganine 4 µM; sphingosine 6.4 µM). Both sphinganine and sphingosine at high concentrations (8–10 lM) arrested the cell cycle at G₂/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 µM) 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.

Key Words: sphinganine • sphingosine • breast cancer • stem cells • apoptosis • differentiation