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

Abstract

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.

Cancer-Selective Targeting and Cytotoxicity by Liposomal-Coupled Lysosomal Saposin C Protein

“…Sphinganine and sphingosine were significantly up-regulated, suggesting that these lipids may also participate in saposin C-dioleoylphosphatidylserine-mediated cell death. These sphingolipids are known to induce apoptosis in human cancer cells, including breast and rhabdomyosarcoma, through caspases (42,43). This is an intriguing finding because saposin C-dioleoylphosphatidylserine may induce apoptosis through elevation of multiple sphingolipids.…”

Milk intelligence: Mining milk for bioactive substances associated with human health

“…The sphingoid bases sphingosine and sphinganine were shown to preferentially inhibit breast cancer cells and eliminate stem cells from which most breast cancer cells arise (Ahn, Chang, & Schroeder, 2006). In contrast, sphingosine-1-phosphate has been shown to stimulate cell growth and suppress apoptosis by acting through G-protein coupled receptors present on mammalian cells, thus stimulating cell proliferation, angiogenesis and inhibiting apoptosis (Oskouian & Saba, 2007;Spiegel & Milstien, 2003).…”

Cancer stem cell markers in common cancers – therapeutic implications

“…Thus, novel small molecules and specific antibodies have the potential not only to reduce tumor mass but also to eradicate the self-renewable source of CSCs [109,110]. Examples include the reduction of the SP fraction of metastatic UMSCC10B and HN12 head and neck cancer cell lines by (i) the targeting or inhibiting of membraneanchored tyrosine kinase receptor signaling by EGFR and Her2/Neu [111,112] and (ii) the supra-additive combinatorial treatment of prostate cancer cell PC-3 xenographs in mice, which combines docetaxel or the anti-EGFR antibody cetuximab with sunitinib malate (SU11248), an oral multi-tyrosine kinase receptor block targeting vascular endothelial growth factor (VEGF)-1, -2 and -3/plateletderived growth factor (PDGF)-a and -b/KIT/FLT-3 [113].…”