Cell membrane signaling as target in cancer therapy: inhibitory effect of N,N-dimethyl and N,N,N-trimethyl sphingosine derivatives on in vitro and in vivo growth of human tumor cells in nude mice.
Cell membrane signaling as target in cancer therapy: inhibitory effect of N,N-dimethyl and N,N,N-trimethyl sphingosine derivatives on in vitro and in vivo growth of human tumor cells in nude mice.
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发表时间：
1991-03
期刊：
影响因子：
11.2
通讯作者：
K. Endo;Yasuyuki Igarashi;Mohammad Nisar;Qinghong Zhou;Sen-itiroh Hakomori
中科院分区：
文献类型：
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作者：
K. Endo;Yasuyuki Igarashi;Mohammad Nisar;Qinghong Zhou;Sen-itiroh Hakomori
鞘氨醇（SPN）被认为是通过蛋白激酶C（PK-C）或一些尚未确定的机制的跨膜信号传导的负调节剂[综述见Y. A. Hannun和R. M. Bell，Science（华盛顿DC），243：500-507，1989]。最近发现N，N-二甲基鞘氨醇（DMS）是一种生理细胞成分，与SPN相比，DMS对A431细胞的PK-C活性显示出更强的立体特异性抑制作用（综述见Y. Igarashi，Trends Glycosci. Glycotechnol，2：319-332，1990;和S. Hakomori，生物化学杂志，265：18713-18716，1990）。（4 E）-N，N，N-三甲基-D-胆甾-鞘氨醇（TMS）作为正常细胞组分是不可检测的;然而，由于其季铵离子结构，预期其表现出有效活性，并且实际上其在体外对PK-C活性（其在细胞生长调节中起重要作用）显示出比DMS或SPN强得多的抑制作用。鉴于这些发现，我们研究了SPN，DMS和TMS对各种人癌细胞系的体外生长和对无胸腺nu/nu小鼠体内肿瘤生长的影响。DMS和TMS在体外和体内对肿瘤细胞的生长抑制作用相似，但TMS对A431细胞PK-C活性的抑制作用比DMS强得多。相反，SPN仅显示出对体外细胞生长的微弱影响，并且对体内肿瘤生长没有影响。皮下注射后的肿瘤生长用人胃癌细胞系MKN 74接种小鼠以剂量依赖性方式被DMS抑制，并且在每天连续注射0.5 mg剂量的DMS或TMS三次或四次后肿瘤大小减小。在停止给予这些化合物后发生肿瘤生长增加;然而，肿瘤的大小仍然显著小于用SPN或对照盐水处理的组。DMS或TMS对体外或体内MKN 74细胞生长的作用强于8-氯-腺苷-环3 '：5'-单磷酸二水合物，8-氯-腺苷-环3 '：5'-单磷酸二水合物是目前在临床试验中用于通过诱导分化抑制肿瘤生长的最有前途的药剂。这些结果表明，DMS或TMS可能是有用的抗癌剂，通过修改跨膜信号相关的癌细胞生长。
Sphingosine (SPN) has been claimed to be a negative modulator of transmembrane signaling through protein kinase C (PK-C) or some yet unidentified mechanism [for review see Y. A. Hannun and R. M. Bell, Science (Washington DC), 243: 500-507, 1989]. N,N-Dimethylsphingosine (DMS) was recently found to be a physiological cellular component and, in comparison to SPN, to show a stronger and stereospecific inhibitory effect on PK-C activity of A431 cells (for review see Y. Igarashi, Trends Glycosci. Glycotechnol., 2: 319-332, 1990; and S. Hakomori, J. Biol. Chem., 265: 18713-18716, 1990). (4E)-N,N,N-Trimethyl-D-erythro-sphingenine (TMS) is not detectable as a normal cellular component; however, it is expected to exhibit potent activity because of its quaternary ammonium ion structure, and in fact it showed much stronger inhibitory effect than DMS or SPN on PK-C activity (which plays an important role in cell growth regulation) in vitro. In view of these findings, we investigated the effects of SPN, DMS, and TMS on in vitro growth of various human carcinoma cell lines and on in vivo tumor growth in athymic nu/nu mice. Both DMS and TMS showed similar in vitro and in vivo growth inhibitory effects on tumor cells, despite the fact that TMS showed a much stronger inhibitory effect than DMS on PK-C activity of A431 cells. In contrast, SPN showed only a weak effect on in vitro cell growth and no effect on in vivo tumor growth. Tumor growth following s.c. inoculation of mice with human gastric carcinoma cell line MKN74 was inhibited in a dose-dependent manner by DMS, and tumor size was decreased after three or four consecutive daily injections of 0.5-mg doses of DMS or TMS. Increased tumor growth occurred after administration of these compounds was stopped; however, size of tumor remained significantly smaller than in groups treated with SPN or control saline. The effect of DMS or TMS on in vitro or in vivo MKN74 cell growth was stronger than that of 8-chloro-adenosine-cyclic 3':5'-monophosphate dihydrate, the most promising agent currently being used in clinical trials for inhibition of tumor growth by induction of differentiation. These results suggest that DMS or TMS could be useful anticancer agents through modification of transmembrane signaling related to cancer cell growth.