Apoptosis induction therapy for pancreatic cancer cells by isoprenoids

类异戊二烯诱导胰腺癌细胞凋亡

• 批准号: 10670491
• 负责人: TERUI Takeshi
• 金额: $ 1.15万
• 依托单位: Sapporo Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670491/
• 关键词: pancreatic cancer; isoprenoid; apoptosis; caspase; G protein

Geranylgeraniol (GGO) and farnesol (FO), synthetic isoprenoids, which are the side chain of vitamine K2, have been noted for their growth inhibitory-effect on hematological cells. However, the precise mechanisms of their functions are still unclear.We investigated the effect of GGO and FO on the proliferation of sex pancreatic cancer cell lines (Panc-1, MIAPaCa-2, AsPC-I, BxPC-3, 1B2C6, KP4) and fresh cancer cells, which were isolated from ascitis of three pancreatic cancer patients. GGO inhibited the proliferation of all these cancer cells at 20-70μM of IC50 and FO did at 20-60μM of IC50. GGO and FO stimulated DNA fragmentation of treated cells. Therefore, we studied on the signal transudation of apoptosis induced by GGO and FO. P53 is not to be implicated to apoptosis by GGO and FO, because all cell lines have deletion or mutation on p53 gene. We studied whether caspse family (ICE and CPP32) was involved in the effect of GGO or FO by using ICE and CPP32 inhibitors. Effect of GGO and FO were not affected by both inhibitors. Pancreatic cancer cells were inoculated in nude mise to study the effect of GGO and FO diminished the cancer tumors without obvious side effects.

香叶基香叶醇 (GGO) 和金合欢醇 (FO) 是合成类异戊二烯，是维生素 K2 的侧链，因其对血液细胞的生长抑制作用而闻名。然而，其功能的确切机制仍不清楚。我们研究了GGO和FO对性胰腺癌细胞系（Panc-1、MIAPaCa-2、AsPC-I、BxPC-3、1B2C6、KP4）和从三名胰腺癌患者腹水中分离的新鲜癌细胞增殖的影响。 GGO 在 IC50 为 20-70μM 时抑制所有这些癌细胞的增殖，而 FO 在 IC50 为 20-60μM 时抑制所有这些癌细胞的增殖。 GGO 和 FO 刺激处理细胞的 DNA 断裂。因此，我们对GGO和FO诱导细胞凋亡的信号转导进行了研究。 P53与GGO和FO的细胞凋亡无关，因为所有细胞系都存在p53基因的缺失或突变。我们通过使用 ICE 和 CPP32 抑制剂研究了 caspse 家族（ICE 和 CPP32）是否参与 GGO 或 FO 的作用。 GGO 和 FO 的效果不受两种抑制剂的影响。将胰腺癌细胞接种于裸鼠中，研究GGO和FO对癌症肿瘤的消减作用，且无明显副作用。

项目成果

KOBAYASHI,D., et al: "Suppression of Intracellular resistance factors by adriamycin augments heat-induced apoptosis via interleukin-1β-converting enzyme activation in pancreatic carcinoma cells"Int J Cancer. 76. 552-555 (1998)

KOBAYASHI，D.等人：“阿霉素对细胞内抵抗因子的抑制通过胰腺癌细胞中白细胞介素-1β-转换酶的激活增强热诱导的细胞凋亡”Int J Cancer. 76. 552-555 (1998)。

Niitsu Y,et al: "A proof of glutathione S-transferase-π-related multidrug resistance by transfer of antisense gene to cancer cells and sense gene to bone marrow stem cell."Chem Biol Interact.. 24. 325-332 (1998)

Niitsu Y 等人：“通过将反义基因转移到癌细胞并将有义基因转移到骨髓干细胞来证明谷胱甘肽 S-转移酶-π 相关的多药耐药性。”Chem Biol Interact.. 24. 325-332 (1998 ）

Sato T, et al: "An apoptosis-inducing gene therapy for pancreatic cancer with a combination of 55-kDa receptor gene transfection and mutein TNF administration"Cancer Res. 58. 1677-1683 (1998)

Sato T 等人：“结合 55-kDa 受体基因转染和突变蛋白 TNF 给药的胰腺癌凋亡诱导基因疗法”Cancer Res。

Hirayama Y, et al: "Concentrations of thrombopoietin in bone marrow in normalsubjexts and in patients with idiopathic thrombocytopenic purpura, apalastic anemia, and essential thrombocythemia correlate with its mRNA"Blood. 92. 46-52 (1998)

Hirayama Y 等人：“正常受试者和特发性血小板减少性紫癜、再生障碍性贫血和原发性血小板增多症患者的骨髓中血小板生成素浓度与其 mRNA 相关”。

HIRAYAMA,Y., et al: "Concentrations of thrombopoietin in bone marrow in normal subjects and in patients with idiopathic thrombocytopenic purpura, aplastic anemia, and essential thrombocythemia correlate with its mRNA expression of bone marrow stromal cell

HIRAYAMA,Y. 等人：“正常受试者和特发性血小板减少性紫癜、再生障碍性贫血和原发性血小板增多症患者的骨髓中血小板生成素浓度与其骨髓基质细胞 mRNA 表达相关