Development of a novel anti-cancer agent from a novel tyrosine kinase inhibitor

从新型酪氨酸激酶抑制剂开发新型抗癌剂

• 批准号: 13672297
• 负责人: NAKAYA Kazuyasu
• 金额: $ 2.24万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672297/
• 关键词: anticancer agent; cancer; Tyrosine kinase; apoptosis; shikonin

We reported previously that β-hydroxyisovalerylshikonin (β-HIVS), isolated from the plant Lithospermium radix, inhibits protein tyrosine kinase activites of EGFR and v-Src. In an effort to enhance the antMumor activity of β-HIVS, we examined the effects of various combinations of β-HIVS with anti-tumor agents on human small-cell lung carcinoma DMS114. β-HIVS and cisplatin (CDDP) had a synergistic inhibitory effect on DMS114 cells, as well as on human leukemia U937 and epidermoid carcinoma A431 cells, while β-HIVS and CDDP alone at the same respective concentrations had little effect. Growth inhibition was accompanied by induction of apoptosis, as determined by an ELISA for detection of cell-death and the TUNEL assay. Using phosphotyrosine-specific antibodies (PY20), we observed that tyrosine kinase activity in DMS114 cells was inhibited by treatment with β-HIVS and CDDP together. The tyrosine kinase activity of isolated Src and that of isolated receptors for epidermal growth factor were also inhibited by the two agents together. The synergistic effects on growth of DMS114 cells of β-HIVS and CDDP were not due simply to the intracellular accumulation of CDDP or to levels of DNA adducts. Our data suggest that the synergistic effect on the growth of DMS114 cells of β-HIVS and CDDP might be a result of inhibition of a tyrosine kinase-dependent pathway.

我们曾报道从紫草中分离得到的β-羟基异戊酰紫草素（β-HIVS）对EGFR和v-Src蛋白酪氨酸激酶活性有抑制作用。为了增强β-HIVS的抗肿瘤活性，我们研究了β-HIVS与抗肿瘤药物的各种组合对人小细胞肺癌DMS 114的作用。β-HIVS与顺铂（CDDP）对人白血病细胞株U937和人表皮样癌细胞株A431的生长抑制作用相同，但两者单独应用时作用不明显。生长抑制伴随细胞凋亡的诱导，如通过用于检测细胞死亡的ELISA和TUNEL测定所确定的。利用酪氨酸磷酸化特异性抗体（PY 20），观察到β-HIVS和CDDP联合作用可抑制DMS 114细胞酪氨酸激酶活性。酪氨酸激酶活性的分离的Src和分离的表皮生长因子受体也被两种药物一起抑制。β-HIVS和CDDP对DMS 114细胞生长的协同作用不仅与CDDP在细胞内的蓄积有关，也与DNA加合物的水平有关。提示β-HIVS和CDDP对DMS 114细胞生长的协同作用可能是通过抑制酪氨酸激酶依赖性途径实现的。

项目成果

Sachiko KAJIMOTO, et al.: "Sophoranone induces apoptosis in human leukemia U937 cells via formation of reactive oxygen species and opening of transition pores"Int. J. Cancer. (in press).

Sachiko KAJIMOTO 等人：“槐酮通过活性氧的形成和过渡孔的开放诱导人白血病 U937 细胞凋亡”Int.

Sachiko Kajimoto et al.: "β-Hydroxyisovalerylshikonin is a novel and potent inhibitor of protein tyrosine kinases"Jpn. J. Cancer Res.. 93(8). 944-951 (2002)

Sachiko Kajimoto 等人：“β-羟基异戊酰紫草素是一种新型且有效的蛋白酪氨酸激酶抑制剂”Jpn. J. Cancer Res. 93(8) (2002)。

Y.S.Kuppumbatti, et al.: "CRBP suppresses breast cancer cell survival and anchorage-independent growth"Oncogene. 20. 7413-7419 (2001)

Y.S.Kuppumbatti 等人：“CRBP 抑制乳腺癌细胞存活和不依赖贴壁的生长”癌基因。

Ying Xu et al.: "Effect of β-hydroxyisovalerylshikonin and cancer chemotherapeutic agents on leukemia U937 and lung cancer DMS114 cells in vitro"The Showa University of Medical Sciences. (3)(in press).

Ying Xu等：“β-羟基异戊酰紫草素和癌症化疗药物对白血病U937和肺癌DMS114细胞的体外作用”昭和医科大学（3）（出版中）。

Ying Xu, Shigeo Nakajo, and Kazuyasu Nakaya: "Effect of p-hydroxyisovalerylshikonin and cancer chemotherapeutic agents on leukemia U937 and lung cancer DMS114 cells in vitro"The Showa University of Medical Sciences. (3). In press.

Ying Xu、Shigeo Nakajo 和 Kazuyasu Nakaya：“对羟基异戊酰紫草素和癌症化疗药物对体外白血病 U937 和肺癌 DMS114 细胞的影响”昭和医科大学。