Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer

Abstract

// Zheng-Zhi Zou 1, 3, * , Pei-Pei Nie 1, 4, * , Ya-Wei Li 5 , Ben-Xin Hou 6 , Rui-Li 5 , Xin-Peng Shi 2 , Zhao-Kui Ma 1, 3 , Bao-Wei Han 5 , Xiao-Yong Luo 2 1 MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China 2 Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China 3 Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, South China Normal University, Guangzhou, China 4 KingMed Diagnostics and KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China 5 Surgical department, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China 6 Department of General Surgery, Hainan Province Nongken Sanya Hospital, Sanya, China * These authors have contributed equally to this work Correspondence to: Xiao-Yong Luo, e-mail: xiaoyongluo68@163.com Keywords: salinomycin, gefitinib, synergistic, apoptosis, resistance, colorectal cancer Received: June 25, 2015      Accepted: September 09, 2015      Published: October 07, 2015 ABSTRACT 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.