title: Prodrug-Like, PEGylated Protein Toxin Trichosanthin for Reversal of Chemoresistance.
abstract: Multidrug resistance (MDR) is a main obstacle in cancer chemotherapy. The MDR mechanisms involve P-glycoprotein (P-gp) overexpression, abnormality of apoptosis-related protein, and altered expression of drug-targeting proteins. Therapeutic proteins are emerging as candidates for overcoming cancer MDR because of not only their large molecular size that potentially circumvents the P-gp-mediated drug efflux but also their distinctive bioactivity distinguished from small-molecular drugs. Herein we report trichosanthin, a plant protein toxin, possesses synergistic effect with paclitaxel (PTX) in the PTX-resistance A549/T nonsmall cell lung cancer (NSCLC) cells, by reversing PTX-caused caspase 9 phosphorylation and inducing caspase 3-dependent apoptosis. Moreover, via intein-mediated site-specific protein ligation, a matrix metalloproteinase (MMP)-activatable cell-penetrating trichosanthin delivery system was constructed by modification of a cell-penetrating peptide and MMP-2-sensitive PEGylation to overcome the limitation of in vivo application of trichosanthin, by improving the short half-life and poor tumor targeting, as well as immunogenicity. In a mouse model bearing A549/T tumor, the MMP-activatable trichosanthin was further tested for its application for MDR reversal in combination with PTX liposomes. The delivery system showed synergy effect with PTX-loaded liposome in treating MDR cancer in vivo.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 501 Hai-ke Rd, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Yingzhi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 501 Hai-ke Rd, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 501 Hai-ke Rd, Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Hongyue
authors.initials: H
authors.lastname: Jin
authors.affiliation: Guangzhou University of Chinese Medicine, Tropical Medical Institute , 12 Ji-chang Rd, Guangzhou 510450, China.
authors.forename: Yisi
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Guangzhou University of Chinese Medicine, Tropical Medical Institute , 12 Ji-chang Rd, Guangzhou 510450, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Wu
authors.affiliation: Guangzhou University of Chinese Medicine, Tropical Medical Institute , 12 Ji-chang Rd, Guangzhou 510450, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Xu
authors.affiliation: University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Yongzhuo
authors.identifier: 0000-0001-7067-8915
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017239:Paclitaxel / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D015978:Trichosanthin / Q000737:chemistry*
chemical_list: D011355:Prodrugs; D011092:Polyethylene Glycols; D015978:Trichosanthin; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020782:Matrix Metalloproteinases; D017239:Paclitaxel
keywords: PEGylation; caspase 9 phosphorylation; intein-mediated protein ligation; matrix metalloproteinase; multidrug resistance; paclitaxel; trichosanthin