Antagonistic effects of sodium butyrate and N-(4-hydroxyphenyl)-retinamide on prostate cancer
Antagonistic effects of sodium butyrate and N-(4-hydroxyphenyl)-retinamide on prostate cancer
复制标题
DOI：
10.1593/neo.06766
复制
发表时间：
2007-03-01
期刊：
影响因子：
4.8
通讯作者：
Buechele, Berthold
中科院分区：
文献类型：
--
作者：
Kuefer, Rainer;Genze, Felicitas;Buechele, Berthold
丁酸盐和类维生素A是很有前途的抗肿瘤药物。在这里，我们分析了丁酸钠和N-（4-羟基苯基）-维甲酰胺（4-HPR）作为单一药物或组合在体外和体内对前列腺癌细胞的影响。丁酸钠和4-HPR对体外培养的前列腺癌细胞具有浓度依赖性的生长抑制作用。等效线图分析表明，丁酸钠和4-HPR一起给药，相互拮抗作用。对于体内研究，产生了水溶性复合物（4-HPR与环糊精）。单剂量丁酸钠和4-HPR在30分钟内在鸡血浆中显示出峰值水平。这两种化合物诱导鸡胚绒毛尿囊膜异种移植物的增殖和凋亡的抑制。联合使用的药物的细胞毒性作用的分析表明，对增殖的抑制和对细胞凋亡的诱导具有拮抗作用。丁酸钠和4-HPR诱导的Jun N-末端激酶磷酸化延长，当这两种化合物联合使用时强烈减弱。两种化合物均诱导NF-κ B的抑制。当化合物组合使用时，这种作用在LNCaP细胞中被强烈拮抗。这些结果表明，尽管单药治疗的结果很有希望，但由于临床环境中的潜在拮抗作用，必须仔细研究联合治疗。
Butyrates and retinoids are promising antineoplastic agents. Here we analyzed effects of sodium butyrate and N-(4-hydroxyphenyl)-retinamide (4-HPR) on prostate cancer cells as monotherapy or in combination in vitro and in vivo. Sodium butyrate and 4-HPR induced concentration-dependent growth inhibition in prostate cancer cells in vitro. The isobologram analysis revealed that sodium butyrate and 4-HPR administered together antagonize effects of each other. For the in vivo studies, a water-soluble complex (4-HPR with a cyclodextrin) was created. A single dose of sodium butyrate and 4-HPR showed a peak level in chicken plasma within 30 minutes. Both compounds induced inhibition of proliferation and apoptosis in xenografts of the chicken chorioallantoic membrane. Analysis of the cytotoxic effects of the drugs used in combination demonstrated an antagonistic effect on inhibition of proliferation and on induction of apoptosis. Prolonged jun N-terminal kinase phosphorylation induced by sodium butyrate and 4-HPR was strongly attenuated when both compounds were used in combination. Both compounds induced inhibition of NF-kappa B. This effect was strongly antagonized in LNCaP cells when the compounds were used in combination. These results indicate that combinational therapies have to be carefully investigated due to potential antagonistic effects in the clinical setting despite promising results of a monotherapy.