Journal
MOLECULAR PHARMACEUTICS
Volume 14, Issue 5, Pages 1429-1438Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.6b00987
Keywords
multidrug resistance; trichosanthin; matrix metalloproteinase; paclitaxel; caspase 9 phosphorylation; intein-mediated protein ligation; PEGylation
Funding
- 973 Program, China [2014CB931900, 2013CB932503]
- NSFC, China [81172996, 81422048, 81521005, 81673382]
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Multidrug resistance (MDR) is a main obstacle in cancer chemotherapy. The MDR mechanisms involve P-glycoprotein (P-gp) overexpression, abnormality of,apoptoiis-related protein, and altered expression of drug-targeting proteihs. Therapeutic proteins ate 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 paditaxeI (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 apopiosis. 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.
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