title: Synergistic induction of apoptosis by salinomycin and gefitinib through lysosomal and mitochondrial dependent pathway overcomes gefitinib resistance in colorectal cancer.
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.
authors.affiliation: MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.|Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, South China Normal University, Guangzhou, China.
authors.forename: Zheng-Zhi
authors.initials: ZZ
authors.lastname: Zou
authors.affiliation: MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.|KingMed Diagnostics and KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China.
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Nie
authors.affiliation: Surgical department, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Ya-Wei
authors.initials: YW
authors.lastname: Li
authors.affiliation: Department of General Surgery, Hainan Province Nongken Sanya Hospital, Sanya, China.
authors.forename: Ben-Xin
authors.initials: BX
authors.lastname: Hou
authors.affiliation: Surgical department, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.lastname: Rui-Li
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Xin-Peng
authors.initials: XP
authors.lastname: Shi
authors.affiliation: MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China.|Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, South China Normal University, Guangzhou, China.
authors.forename: Zhao-Kui
authors.initials: ZK
authors.lastname: Ma
authors.affiliation: Surgical department, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Bao-Wei
authors.initials: BW
authors.lastname: Han
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Luo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002401:Cathepsin B / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D000077156:Gefitinib; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D011714:Pyrans / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D002401:Cathepsin B; D002402:Cathepsin D; D000077156:Gefitinib; D011714:Pyrans; D011799:Quinazolines; D017382:Reactive Oxygen Species; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: apoptosis; colorectal cancer; gefitinib; resistance; salinomycin; synergistic