Ahn Eun Hyun, Chang Chia-Cheng, Schroeder Joseph J
University of Pennsylvania School of Medicine, Department of Pathology and Laboratory Medicine, 506 Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, USA.
Exp Biol Med (Maywood). 2006 Nov;231(10):1664-72. doi: 10.1177/153537020623101012.
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.
尚无关于鞘脂代谢产物对正常人乳腺上皮细胞、干细胞和致瘤细胞的增殖及分化影响的比较研究报道。本研究的目的是使用一种新型细胞培养系统来评估鞘氨醇碱（鞘氨醇和二氢鞘氨醇）的化疗和化学预防潜力，该系统包括从健康女性在缩乳术中获得的乳腺组织中培养出的正常人乳腺上皮细胞（HBEC）（具有干细胞特征的I型HBEC和具有基底上皮细胞表型的II型HBEC）以及转化的致瘤性I型HBEC。结果表明，二氢鞘氨醇比鞘氨醇更有效地抑制转化的致瘤性I型HBEC的生长并诱导其凋亡（二氢鞘氨醇的IC50为4μM；鞘氨醇为6.4μM）。高浓度（8 - 10μM）的二氢鞘氨醇和鞘氨醇均使细胞周期停滞在G2/M期。二氢鞘氨醇比鞘氨醇更强烈地抑制I型HBEC的生长并导致其死亡。相比之下，II型HBEC（正常分化细胞）对鞘氨醇碱生长抑制作用的敏感性低于I型HBEC（干细胞）或转化的致瘤性I型HBEC，这表明鞘氨醇碱可能用作化疗药物。在低于生长抑制范围的浓度（0.05、0.1和0.5μM）下，鞘氨醇碱诱导I型HBEC向II型HBEC分化，这通过形态学检测以及肿瘤抑制蛋白maspin的表达得以证实，maspin是II型HBEC的标志物。因此，鞘氨醇碱可能通过优先抑制癌细胞并消除产生大多数乳腺癌细胞的干细胞，发挥化疗和化学预防药物的作用。
