Antitumor and antimetastatic activities of 4-hydroxyderricin isolated from Angelica keiskei roots
Antitumor and antimetastatic activities of 4-hydroxyderricin isolated from Angelica keiskei roots
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DOI：
10.1055/s-2004-815537
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发表时间：
2004-03-01
期刊：
影响因子：
2.7
通讯作者：
Baba, K
中科院分区：
文献类型：
--
作者：
Kimura, Y;Taniguchi, M;Baba, K
Angelica keiskei Koizumi（伞形科）的根传统上被用作保健食品，被认为具有利尿、通便、兴奋和催乳作用。最近，人们认为明日葵的根和草药具有预防冠心病、高血压和癌症的作用。据报道，从该根中分离出查尔酮衍生物，例如黄当归醇和4-羟基德里素。最近，我们报道了 50% 乙醇提取物、乙酸乙酯可溶部分和分离的黄当归醇可抑制 Lewis 肺癌 (LLC) 小鼠的肿瘤生长和肺部转移。在本研究中，我们研究了 4-羟基德里蛋白对皮下或脾内 LLC 植入的 C57BL/6J 雌性小鼠肿瘤生长和肺或肝转移的影响。口服4-Hydroxyderricin 50mg/kg×2/天可抑制LLC皮下植入小鼠的肿瘤生长，并抑制手术切除皮下肿瘤后小鼠的肺转移，延长小鼠的生存时间。阿霉素（5 mg/kg x 2/周，腹腔注射）抑制肿瘤生长和肺转移，但与 4-羟基德里霉素治疗的小鼠相比，它缩短了小鼠的生存时间并降低了生存率。 100μM浓度的4-Hydroxyderricin抑制LLC细胞的DNA合成，但对人脐静脉内皮细胞(HUVEC)的DNA合成或LLC细胞与HUVEC的粘附没有影响。浓度为 10 至 100 μM 的 4-Hydroxyderricin 可抑制基质胶诱导的 HUVEC 毛细血管样管的形成。通过口服4-羟基德里霉素，皮下植入LLC的小鼠的脾脏和胸腺重量保持接近正常小鼠的重量。此外，4-Hydroxyderricin (50mg/kg x 2/day) 抑制肿瘤切除小鼠脾脏中淋巴细胞、CD4(+)、CD8(+) 和自然杀伤 (NK)-T 细胞数量的减少。与 LLC 切除小鼠相比，阿霉素减少了淋巴细胞、CD4(+)、CD8(+) 和 NK 细胞的数量。这些结果表明，4-羟基德里霉素的抗肿瘤和抗转移活性可能通过免疫系统和抑制血管生成来调节。
The roots of Angelica keiskei Koizumi (Umbelliferae) have traditionally been used as a health food considered to have diuretic, laxative, analeptic and lactagogue effects. Recently, it has been thought that the roots and herbs of A. keiskei have preventive effects against coronary heart disease, hypertension and cancer. It has been reported that chalcone derivatives, such as xanthoangelol and 4-hydroxyderricin, are isolated as main components from this root. Recently, we reported that the 50% ethanol extract, the ethyl acetate-soluble fraction and the isolated xanthoangelol, inhibited tumor growth and metastasis to the lung in Lewis lung carcinoma (LLC)-bearing mice. In the present study, we examined the effects of 4-hydroxyderricin on tumor growth and metastasis to the lung or liver in subcutaneous or intrasplenic LLC-implanted C57BL/6J female mice. 4-Hydroxyderricin at a dose of 50mg/kg x 2/day orally inhibited the tumor growth in subcutaneous LLC-implanted mice and inhibited the lung metastasis and prolonged the survival time in mice after the removal of subcutaneous tumors by surgical operation. Doxorubicin (5 mg/kg x 2/week, i.p.) inhibited the tumor growth and metastasis to the lung, but it shortened the survival time and reduced the survival rate compared to those in 4-hydroxyderricin-treated mice. 4-Hydroxyderricin inhibited DNA synthesis in LLC cells at a concentration of 100 muM, but it had no effect on the DNA synthesis in human umbilical vein endothelial cells (HUVECs) or on the adherence of LLC cells to HUVECs. 4-Hydroxyderricin inhibited Matrigel-induced formation of capillary-like tubes by HUVECs at concentrations of 10 to 100 muM. The weights of the spleen and thymus in mice with subcutaneously implanted LLC were maintained close to those of normal mice by orally administered 4-hydroxyderricin. In addition, 4-hydroxyderricin (50mg/kg x 2/day) inhibited the reduction of the numbers of lymphocytes, CD4(+), CD8(+) and natural killer (NK)-T cells in the spleen of tumor-removed mice. Doxorubicin reduced the numbers of lymphocytes, CD4(+), CD8(+) and NK cells compared to those in LLC-removed mice. These results suggest that the antitumor and antimetastatic activities of 4-hydroxyderricin may be modulated by the immune system and the inhibition of angiogenesis.