title: Cell-penetrating peptides induce apoptosis and necrosis through specific mechanism and cause impairment of Na+-K+-ATPase and mitochondria.
abstract: Cell-penetrating peptides (CPPs) are widely used in the development of various drug delivery systems because of their ability of penetrating plasma membrane. However, the safety of their application remains largely unknown. In this study, we found that the incubation of two main kinds of CPPs with human normal liver cells could cause the occurrence of apoptosis and necrosis, then the detailed apoptosis-related protein were detected out. To discover the specific way which leads to these results, several methods were used in this study. Several cytokines, such as Caspase3 and Bcl-2, were detected to prove that the damage happened after treated with different CPPs. Then shielding the positive charge of TAT and R8, depletion of Na+in culturing medium and addition of several inhibitors of specific ATPase site were used to investigate whether the cytotoxicity were charge-dependent and ATPase-related. Furthermore, the membrane potential of mitochondria and the leakage of mitochondrial cytochrome c were detected after treated with CPPs to investigate the damage on mitochondria. In general, our results assess the cytotoxicity caused by two main kinds of CPPs and reveal the clear mechanism of how it occurs. This study reveals the essence of cytotoxicity caused by CPPs, and the methods we followed can be used to evaluate the biocompatibility of new-designed CPPs, which makes the application of CPPs better and safer.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Qianwen
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Kairong
authors.initials: K
authors.lastname: Shi
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Xianyang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Yayuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Jiajing
authors.initials: J
authors.lastname: Tang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People's Republic of China. qinhe@scu.edu.cn.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D005333:Fetus; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C000595707:BCL2 protein, human; D057846:Cell-Penetrating Peptides; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C500307:octa-arginine peptide; D054322:tat Gene Products, Human Immunodeficiency Virus; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium
keywords: Apoptosis; Cell-penetrating peptide; Mitochondria; Na+–K+-ATPase; Necrosis