Molecular mechanism of bone metastasis in prostate cancer

前列腺癌骨转移的分子机制

• 批准号: 14571491
• 负责人: KOSHIDA Kiyoshi
• 金额: $ 2.24万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571491/
• 关键词: prostate cancer; bone metastasis; bisphosphonate; hormone refractory; ホルモン反応性

Bisphosphonates are well established for the management of cancer-induced skeletal complications.Recent studies suggest that bisphosphonates promote apoptosis of cancer cells as well as osteoclasts in bone metastatic sites.In the present study, to determine the direct effects of bisphosphonate on prostate cancer cells, we examined the effects of minodronate on prostatic cancer cell growth and the expression of apoptosis related proteins and osteoclastogenic factors.PC-3, DU 145 and LNCaP cells were treated with amino-bisphosphonate minodronate.Then proliferation, apoptosis and expression of bcl-2, bax, poly(ADP)-ribose polymerase(PARP), caspase-3, receptor activator of nuclear factor-kB ligand(RANKL), osteoprotegerin(OPG), matrix metalloproteinases-2(MMP-2), and parathyroid hormone related protein(PTHrP)were assessed. The proliferation of LNCaP, DU145 and PC-3 cells were inhibited by minodronate.DNA fragmentation and TUNEL positive nuclei were observed in minodronate treated PC-3 cells.Minodronate decreased bax expression and induced bcl-2 expression, caspase-3 activity and degradation of PARP in DU145 and PC-3 cells. Minodronate decreased expression of RANKL, PTHrP and MMP-2 in PC-3 cells.Antitumor effect of a new bisphosphonate, YM-529 was tested using a mouse model of bone tumor formation created by intratibial injection of hormone refractory LNCaP-SF cells.Antitumor effect of YM-529 on bone tumor formation was evident in a dose-dependent manner as no new osteoid formation was seen in mice treated with YM-529, while tumor cell invasion into bone matrix was remarkable in control mice.Our results suggest that bisphosphonate not only directly promotes prostate cancer cell apoptosis but also decreases pro-osteoclasfic gene expression in prostate cancer cells, and has the potential of an antitumor agent against hormone refractory prostate cancer.

双膦酸类药物用于治疗癌症引起的骨骼并发症。最近的研究表明，双膦酸类药物可促进癌细胞和骨转移部位的破骨细胞的凋亡。本研究旨在探讨双膦酸类药物对前列腺癌细胞的直接作用，并观察其对前列腺癌细胞生长、凋亡相关蛋白和破骨因子表达的影响。用氨基双膦酸盐类药物处理PC-3、DU 145和LNCaP细胞，观察其对PC-3、DU 145和LNCaP细胞的增殖、凋亡和bcl2、bax、多聚(ADP)核糖聚合酶(PARP)、caspase-3、核因子-kB受体激活剂和配体(RANKL)表达的影响。结果表明，双膦酸类药物对PC-3、DU 145和LNCaP细胞的增殖、凋亡和bcl-2、bax、多聚(ADP)-核糖聚合酶(PARP)、caspase-3、核因子-kB受体激活物(RANKL)和破骨因子的表达有明显的影响测定骨保护素(OPG)、基质金属蛋白酶-2(MMP2)和甲状旁腺激素相关蛋白(PTHrP)。米诺磷酸钠可抑制LNCaP、DU145和PC-3细胞的增殖。米诺磷酸钠处理后的PC-3细胞出现DNA断裂和TUNEL阳性核；米诺磷酸钠可降低DU145和PC-3细胞中Bax的表达，诱导BCL-2表达、caspase-3活性和PARP降解。米诺磷酸钠降低PC-3细胞RANKL、PTHrP和MMP2的表达。用激素耐药的LNCaP-SF细胞骨内注射建立的小鼠骨肿瘤模型，检测了新型双膦酸盐YM-529的抗肿瘤作用。YM-529的抗肿瘤作用呈剂量依赖关系，YM-529组小鼠未见新的类骨质形成，而对照组小鼠肿瘤细胞侵袭骨基质明显。结果表明，双膦酸盐不仅直接促进前列腺癌细胞的凋亡，而且还减少了促破骨基因的表达。并且有可能成为治疗激素难治性前列腺癌的抗肿瘤药物。

项目成果

Asahi H, Koshida, et al.: "Bisphosphonate therapy for hormone refractory prostate cancer with bone metastasis"Journal of Urology. 169. 281-282 (2003)

Asahi H、Koshida 等人：“双磷酸盐治疗激素难治性前列腺癌骨转移”泌尿学杂志。

Asahi H.Koshida K.et al.: "Bisphosphonate therapy for hormone refractory prostate cancer with bone metastasis"Journal of Urology. 169. 281-282 (2003)

Asahi H.Koshida K.等人：“双磷酸盐治疗激素难治性前列腺癌骨转移”泌尿外科杂志。

Asahi H, Mizokami A, Maeda Y, Komatsu K, Koshida K, Namiki M.: "Bisphopsphonate therapy for hormone refractory prostate cancer with bone metastasis."Journal of Urology. 169(1). 281-282 (2003)

Asahi H、Mizokami A、Maeda Y、Komatsu K、Koshida K、Namiki M.：“Bisphopsphonate 治疗激素难治性前列腺癌骨转移。”泌尿学杂志。

Asahi H., Koshida K., et al.: "Bisphosphonate therapy for hormone refractory prostate cancer with bone metastasis"Journal of Urology. 169. 281-282 (2003)

Asahi H.、Koshida K. 等人：“双磷酸盐治疗激素难治性前列腺癌骨转移”泌尿学杂志。