Department of Pathology and 2Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA.
Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA.
Int J Oncol. 2019 Feb;54(2):655-664. doi: 10.3892/ijo.2018.4641. Epub 2018 Nov 22.
The overall goal of the present study was to evaluate the chemotherapeutic and cancer‑protective properties of D‑erythro‑sphingosine (sphingosine) and C2‑ceramide using a human breast epithelial cell (HBEC) culture system, which represents multiple‑stages of breast carcinogenesis. The HBEC model includes Type I HBECs (normal stem), Type II HBECs (normal differentiated) and transformed cells (immortal/non‑tumorigenic cells and tumorigenic cells, which are transformed from the same parental normal stem cells). The results of the present study indicate that sphingosine preferentially inhibits proliferation and causes death of normal stem cells (Type I), tumorigenic cells, and MCF7 breast cancer cells, but not normal differentiated cells (Type II). In contrast to the selective anti‑proliferative effects of sphingosine, C2‑ceramide inhibits proliferation of normal differentiated cells as well as normal stem cells, tumorigenic cells, and MCF7 cancer cells with similar potency. Both sphingosine and C2‑ceramide induce apoptosis in tumorigenic cells. Among the sphingosine stereoisomers (D‑erythro, D‑threo, L‑erythro, and L‑threo) and sphinganine that were tested, L‑erythro‑sphingosine most potently inhibits proliferation of tumorigenic cells. The inhibition of breast tumorigenic/cancer cell proliferation by sphingosine was accompanied by inhibition of telomerase activity. Sphingosine at non‑cytotoxic concentrations, but not C2‑ceramide, induces differentiation of normal stem cells (Type I), thereby reducing the number of stem cells that are more susceptible to neoplastic transformation. To the best of our knowledge, the present study demonstrates one of the first results that sphingosine can be a potential chemotherapeutic and cancer‑protective agent, whereas C2‑ceramide is not an ideal chemotherapeutic and cancer‑protective agent due to its anti‑proliferative effects on Type II HBECs and its inability to induce the differentiation of Type I to Type II HBECs.
本研究的总体目标是使用人乳腺上皮细胞（HBEC）培养系统评估 D-erythro-赤藓糖醇（赤藓糖醇）和 C2-神经酰胺的化疗和抗癌特性，该系统代表了乳腺癌发生的多个阶段。HBEC 模型包括 I 型 HBEC（正常干细胞）、II 型 HBEC（正常分化）和转化细胞（永生化/非肿瘤细胞和肿瘤细胞，由同一亲本正常干细胞转化而来）。本研究结果表明，赤藓糖醇优先抑制正常干细胞（I 型）、肿瘤细胞和 MCF7 乳腺癌细胞的增殖并导致其死亡，但不抑制正常分化细胞（II 型）。与赤藓糖醇的选择性抗增殖作用相反，C2-神经酰胺以相似的效力抑制正常分化细胞以及正常干细胞、肿瘤细胞和 MCF7 癌细胞的增殖。赤藓糖醇和 C2-神经酰胺均可诱导肿瘤细胞凋亡。在所测试的赤藓糖醇立体异构体（D-erythro、D-threo、L-erythro 和 L-threo）和神经酰胺中，L-erythro-赤藓糖醇最有效地抑制肿瘤细胞的增殖。赤藓糖醇抑制乳腺肿瘤/癌细胞增殖伴随着端粒酶活性的抑制。赤藓糖醇在非细胞毒性浓度下但不是 C2-神经酰胺可诱导正常干细胞（I 型）分化，从而减少更易发生肿瘤转化的干细胞数量。据我们所知，本研究首次证明赤藓糖醇可能是一种潜在的化疗和抗癌药物，而 C2-神经酰胺不是一种理想的化疗和抗癌药物，因为它对 II 型 HBEC 的抗增殖作用及其不能诱导 I 型向 II 型 HBEC 的分化。
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