title: CQ synergistically sensitizes human colorectal cancer cells to SN-38/CPT-11 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk.
abstract: Autophagy plays a key role in supporting cell survival against chemotherapy-induced apoptosis. In this study, we found the chemotherapy agent SN-38 induced autophagy in colorectal cancer (CRC) cells. However, inhibition of autophagy using a small molecular inhibitor 3-methyladenine (3-MA) and ATG5 siRNA did not increase SN-38-induced cytotoxicity in CRC cells. Notably, another autophagy inhibitor chloroquine (CQ) synergistically enhanced the anti-tumor activity of SN-38 in CRC cells with wild type (WT) p53. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that CQ and SN-38 acted together to trigger reactive oxygen species (ROS) burst, upregulate p53 expression, elicit the loss of lysosomal membrane potential (LMP) and mitochondrial membrane potential (∆ψm). In addition, ROS induced by CQ plus SN-38 upregulated p53 levels by activating p38, conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce CRC cell death. Moreover, we showed induction of ROS and p53 by the two agents provoked the loss of LMP and ∆ψm. Altogether, all results suggested that CQ synergistically sensitized human CRC cells with WT p53 to SN-38 through lysosomal and mitochondrial apoptotic pathway via p53-ROS cross-talk. Lastly, we showed that CQ could enhance CRC cells response to CPT-11 (a prodrug of SN-38) in xenograft models. Thus the combined treatment might represent an attractive therapeutic strategy for the treatment of CRC.
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Pinjia
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Luo
authors.affiliation: KingMed Diagnostics and KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Nie
authors.affiliation: MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, College of Biophotonics, South China Normal University, No. 55 Zhongshan Road West, Guangzhou, China.
authors.forename: Baoyan
authors.initials: B
authors.lastname: Wu
authors.affiliation: KingMed Diagnostics and KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Xinpeng
authors.initials: X
authors.lastname: Shi
authors.affiliation: MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, College of Biophotonics, South China Normal University, No. 55 Zhongshan Road West, Guangzhou, China.
authors.forename: Haocai
authors.initials: H
authors.lastname: Chang
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Oncology, The Affiliated Luoyang Central Hospital of Zhengzhou University, Luoyang, China.
authors.forename: Xiurong
authors.initials: X
authors.lastname: Yu
authors.affiliation: MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, Joint Laboratory of Laser Oncology with Cancer Center of Sun Yat-sen University, College of Biophotonics, South China Normal University, No. 55 Zhongshan Road West, Guangzhou, China. Electronic address: zouzhengzhi@m.scnu.edu.cn.
authors.forename: Zhengzhi
authors.initials: Z
authors.lastname: Zou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077146:Irinotecan; D002738:Chloroquine; D002166:Camptothecin
keywords: Apoptosis; Chloroquine; Colorectal cancer; P53; ROS; SN-38