Docetaxel inhibits bone resorption through suppression of osteoclast formation and fuction in different manners

多西紫杉醇通过不同方式抑制破骨细胞的形成和功能来抑制骨吸收

• 批准号: 18592208
• 负责人: TAKAHASHI Masahiro
• 金额: $ 2.36万
• 依托单位: Matsumoto Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18592208/
• 关键词: DOCETAXEL; BONE RESORPTION; OSTEOBLAST; OSTEOCLAST; MICROTUBULES

Bone-resorbing osteoclasts are differentiated from the monocyte-macrophage lineage cells in response to receptor activator of nuclear factor KB (RANKL) expressed by osteoblasts. Docetaxel (Taxotere^<R>) is widely used for the treatment for many kinds of cancers including breast, ovarian and oral cancers. Using mouse culture systems, we explored the effects of docetaxel on osteoclastic bone resorption. Osteoclasts were formed within 6 days in cocultures of mouse osteoblasts and bone marrow cells in the presence of 1, 25-dihydroxyvitamin D_3 [1, 25(OH)_2D_3] together with prostaglandin B_2 (PGE_2). When cocultures were treated with docetaxel for the entire culture period or for the first 3 days, docetaxel dose-dependently inhibited osteoclast formation induced by 1, 25(OH)_2D_3 plus PGE_2 with the complete inhibition at 10^<-8>M. However, docetaxel even at 10^<-6> added to the coculture for the fmal 3 days slightly inhibited the osteoclast formation. Osteoprotegerin, a decoy receptor of RANKL, added to the coculture for the entire culture period or the fmal 3 days completely inhibited osteoclast formation. Expression of RANKL induced by 1, 25(OH)_2D_3 plus PGE_2 in osteoblasts was not affected by docetaxel even at 10^<-6>M. Docetaxel at 10^<-8>M inhibited proliferation of osteoblasts and bone marrow cells. In contrast, the pit-forming activity of osteoclasts placed on dentine slices was not inhibited by docetaxel even at 10^<-7>M but inhibited at 10^<-6>M or more. These results suggest that docetaxel inhibits bone resorption in two different processes: inhibition of osteoclast formation at 10^<-8>M, and function of mature osteoclasts at 10^<-6>M or more.

骨吸收破骨细胞是响应成骨细胞表达的核因子 KB (RANKL) 受体激活剂而从单核巨噬细胞谱系细胞中分化出来的。多西紫杉醇（Taxotere^<R>）广泛用于治疗多种癌症，包括乳腺癌、卵巢癌和口腔癌。使用小鼠培养系统，我们探讨了多西紫杉醇对破骨细胞骨吸收的影响。在 1, 25-二羟基维生素 D_3 [1, 25(OH)_2D_3] 和前列腺素 B_2 (PGE_2) 存在下，小鼠成骨细胞和骨髓细胞共培养 6 天内形成破骨细胞。当在整个培养期间或前3天用多西紫杉醇处理共培养物时，多西紫杉醇剂量依赖性地抑制由1, 25(OH)_2D_3加PGE_2诱导的破骨细胞形成，并在10 ^ -8 M时完全抑制。然而，即使在最后3天添加到共培养物中的多西紫杉醇甚至以10 1 -6 也轻微抑制破骨细胞形成。骨保护素（RANKL 的一种诱饵受体）在整个培养期间或最后 3 天添加到共培养物中，可完全抑制破骨细胞的形成。即使在10 ^ -6 M下，成骨细胞中由1, 25(OH)_2D_3加PGE_2诱导的RANKL表达也不受多西紫杉醇影响。 10 1 -8 M多西紫杉醇抑制成骨细胞和骨髓细胞的增殖。相反，放置在牙本质切片上的破骨细胞的小凹形成活性即使在10 ^ -7 M时也不被多西紫杉醇抑制，但在10 ^ -6 M或更高时被抑制。这些结果表明多西他赛在两个不同的过程中抑制骨吸收：在10 ^ -8 M时抑制破骨细胞形成，以及在10 ^ -6 M或更高时抑制成熟破骨细胞的功能。

项目成果

Refractory factors in head and neck cancer : ATP binding cassette transportors expressed in head and neck cancer cell lines.

头颈癌的难治因素：头颈癌细胞系中表达的 ATP 结合盒转运蛋白。

• 发表时间: 2006
• 期刊: Oral sci. int. 3(2)
• 作者: Uematsu T;他;Uematsu T
• 通讯作者: Uematsu T

Docetaxel inhibits bone resorption through supression of osteoclast formation and function in different manners.

多西紫杉醇通过以不同方式抑制破骨细胞的形成和功能来抑制骨吸收。

• 发表时间: 2008
• 期刊: JBMM. (in press)
• 作者: Yamaoka M.;他;Yamaoka M;Takahashi M
• 通讯作者: Takahashi M

タキサン系抗癌剤ドセタキセルの腫瘍随伴性骨吸収抑制機構の解明

紫杉烷类抗癌药物多西紫杉醇抑制副肿瘤性骨吸收的机制阐明

• 发表时间: 2007
• 作者: Uematsu T;他;Uematsu T;Naoyuki Takahashi;高橋 昌宏
• 通讯作者: 高橋 昌宏

Docetaxel inhibits bone resorption through supression of osteoclast formation and function in different manners

多西紫杉醇通过不同方式抑制破骨细胞的形成和功能来抑制骨吸收

• 发表时间: 2008
• 期刊: JBMM
• 作者: Takahashi M.;他
• 通讯作者: 他

Multidrug resistance-associated protein 7 expression is involved in cross-resistance to docetaxel in salivary gland adenocarcinoma cell lines.

• DOI: 10.3892/ijo.30.2.393
• 发表时间: 2007-02
• 期刊: International journal of oncology
• 影响因子: 5.2
• 作者: Hiroko Naramoto;T. Uematsu;T. Uchihashi;R. Doto;T. Matsuura;Y. Usui;S. Uematsu;Xianqi Li;Masahiro Takahashi;M. Yamaoka;K. Furusawa