Synthetic Galectin-3 Inhibitor Increases Metastatic Cancer Cell Sensitivity to Taxol-Induced Apoptosis In Vitro and In Vivo
Synthetic Galectin-3 Inhibitor Increases Metastatic Cancer Cell Sensitivity to Taxol-Induced Apoptosis In Vitro and In Vivo
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DOI：
10.1593/neo.09594
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发表时间：
2009-09-01
期刊：
影响因子：
4.8
通讯作者：
Glinsky, Gennadi V.
中科院分区：
文献类型：
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作者：
Glinsky, Vladislav V.;Kiriakova, Galina;Glinsky, Gennadi V.
目前，对于具有晚期转移性疾病的癌症患者没有有效的治愈性疗法。靶向作用于线粒体凋亡途径的抗凋亡分子可能潜在地增强细胞毒性药物的抗转移作用。与Bcl-2家族成员类似，β-半乳糖苷结合凝集素半乳糖凝集素-3通过线粒体途径保护癌细胞免受细胞毒性药物诱导的细胞凋亡。在这项研究中，我们测试的假设，抑制半乳糖凝集素-3抗凋亡功能，使用合成的低分子量碳水化合物为基础的化合物乳果糖-L-亮氨酸（Lac-L-Leu）将增加紫杉醇诱导的人癌细胞凋亡，并增加其对已建立的转移的疗效。单独使用合成糖胺Lac-L-Leu治疗可将已建立的MDA-MB-435 Lung2肺转移瘤的数量减少5.5倍（P = 0.032），但对转移瘤的发生率无显著影响。紫杉醇单独给药（10 mg/kg，3次，间隔3天）对MDA-MB-435 Lung2转移瘤的发生率或数量无显著影响。Lac-L-Leu/紫杉醇联合治疗降低了肺转移的数量（P =.02）和发生率（P =.001），导致无转移动物的数量增加了5倍，从对照组的14%增加到联合治疗组的70%。联合治疗组肺转移的中位数降至0，而对照组为11（P = 0.02）。Lac-L-Leu/紫杉醇组合对转移性细胞中克隆形成存活和诱导凋亡的协同抑制在功能上与线粒体损伤的增加相关，并且足以在56%的实验动物中引起晚期转移性疾病的逆转和根除的抗转移活性。
At present, there is no efficient curative therapy for cancer patients with advanced metastatic disease. Targeting of antiapoptotic molecules acting on the mitochondrial apoptosis pathway could potentially augment antimetastatic effect of cytotoxic drugs. Similarly to Bcl-2 family members, beta-galactoside-binding lectin galectin-3 protects cancer cells from apoptosis induced by cytotoxic drugs through the mitochondrial pathway. In this study, we tested the hypothesis that inhibiting galectin-3 antiapoptotic function using a synthetic low-molecular weight carbohydrate-based compound lactulosyl-L-leucine (Lac-L-Leu) will augment apoptosis induced in human cancer cells by paclitaxel and increase its efficacy against established metastases. Treatment with synthetic glycoamine Lac-L-Leu alone reduced the number of established MDA-MB-435Lung2 pulmonary metastases 5.5-fold (P = .032) but did not significantly affect the incidence of metastasis. Treatment with paclitaxel alone (10 mg/kg three times with 3-day intervals) had no significant effect on the incidence or on the number of MDA-MB-435Lung2 metastases. Treatment with Lac-L-Leu/ paclitaxel combination decreased both the number (P = .02) and the incidence (P = .001)of pulmonary metastases, causing a five-fold increase in the number of metastasisfree animals from 14% in the control group to 70% in the combination therapy group. The median number of lung metastases dropped to 0 in the combination therapy group compared with 11 in the control (P = .02). Synergistic inhibition of clonogenic survival and induction of apoptosis in metastatic cells by Lac-L-Leu/paclitaxel combination was functionally linked with an increase in mitochondrial damage and was sufficient for the antimetastatic activity that caused a reversal and eradication of advanced metastatic disease in 56% of experimental animals.