Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer
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Zheng-Zhi Zou1,3,*, Pei-Pei Nie1,4,*, Ya-Wei Li5, Ben-Xin Hou6, Rui-Li5, Xin-Peng Shi2, Zhao-Kui Ma1,3, Bao-Wei Han5, Xiao-Yong Luo2
1MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China
2Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
3Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, South China Normal University, Guangzhou, China
4KingMed Diagnostics and KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China
5Surgical department, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China
6Department of General Surgery, Hainan Province Nongken Sanya Hospital, Sanya, China
*These authors have contributed equally to this work
Xiao-Yong Luo, e-mail: email@example.com
Keywords: salinomycin, gefitinib, synergistic, apoptosis, resistance, colorectal cancer
Received: June 25, 2015 Accepted: September 09, 2015 Published: October 07, 2015
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.
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