title: A novel antitumour strategy using bidirectional autophagic vesicles accumulation via initiative induction and the terminal restraint of autophagic flux.
abstract: Autophagy is a lysosomal degradation pathway that protects cancer cells from multiple endogenous and extraneous stresses, particularly during the pathogenesis of cancer. An autophagic balance exists in the tumour microenvironment. Appropriate disturbance to this balance may have therapeutic potential. Here, we report a novel antitumour strategy based on an autophagic catastrophic vacuolisation effect in tumour cells. We achieved this effect via initiative induction and the terminal restraint of autophagic flux. The TAT-Beclin 1 peptide (T-B) was constructed for the initiative induction of autophagic flux, whereas hydroxychloroquine (HCQ)-loaded liposomes (HCQ-Lip) were constructed for terminal restraint. We demonstrate that T-B, a new CPP tandem autophagy inducing peptide, effectively activates the autophagy signal at the early stage of the autophagy pathway. HCQ deacidified the lysosome during the final stage of autophagy. We combined T-B and HCQ-Lip to induce autophagic catastrophic vacuolisation and death in several tumour cell lines based on the idea of "broadening sources of income and reducing expenditure". The co-treated group exhibited at least a 1.86-fold greater and up to 5.66-fold greater cytotoxic effect in vitro. In addition, this strategy showed at least a 2.0-fold tumour inhibitory effect compared to the other groups in vivo. Therefore, this bidirectional accumulation of autophagic vesicles exhibited potential efficacy for tumour treatment.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Tai
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Yayuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Huile
authors.initials: H
authors.lastname: Gao
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Kairong
authors.initials: K
authors.lastname: Shi
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Qianyu
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, and State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015696:Gene Products, tat / Q000494:pharmacology; D006886:Hydroxychloroquine / Q000737:chemistry / Q000494:pharmacology; D008081:Liposomes / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D014617:Vacuoles / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D015696:Gene Products, tat; D008081:Liposomes; D010455:Peptides; D006886:Hydroxychloroquine
keywords: Anti-tumour; Autophagic vesicles; Bidirectional accumulation; HCQ liposomes; TAT–Beclin 1