Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer.
Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer.
复制标题
盐霉素和吉非替尼通过溶酶体和线粒体依赖性途径协同诱导细胞凋亡，克服了结直肠癌中的吉非替尼耐药性
DOI：
10.18632/oncotarget.5628
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发表时间：
2017-04-04
期刊：
影响因子：
--
通讯作者：
Luo XY
中科院分区：
文献类型：
--
作者：
Zou ZZ;Nie PP;Li YW;Hou BX;Rui-Li;Shi XP;Ma ZK;Han BW;Luo XY
Here, we showed the antibiotic salinomycin (SAL) combined with GEF exerted synergistic cytotoxicity effects in colorectal cancer cells irrespective of their EGFR and KRAS status, with a relatively low toxicity to normal cells. Additionally, combination of the two drugs overcame Ras-induced resistance and the acquired resistance to GEF. Further, we identified a new potential mechanism of this cooperative interaction by showing that GEF and SAL acted together to enhance production of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP) and lysosomal membrane potential (LMP). And the ROS contributed the loss of MMP and LMP. We also found that GEF and SAL acted in concert to induce apoptosis via a mitochondrial-lysosomal cross-talk and caspase-independent pathway triggered by cathepsin B and D. Lastly, SAL in combination with GEF sensitized GEF-resistant cells to GEF in a nude mouse xenograft model. This novel combination treatment might provide a potential clinical application to overcome GEF resistance in colorectal cancer.
