Studies on the mechanism of action of dextrin−phospholipase A₂and its suitability for use in combination therapy
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Ferguson, Elaine L., Richardson, Simon C.W.
ORCID: 0000-0002-7927-0649
and Duncan, Ruth
(2010)
Studies on the mechanism of action of dextrin−phospholipase A₂and its suitability for use in combination therapy.
Molecular Pharmaceutics, 7 (2).
pp. 510-521.
ISSN 1543-8384 (Print), 1543-8392 (Online)
(doi:https://doi.org/10.1021/mp900232a)
Abstract
The bioresponsive conjugate dextrin−phospholipase A2 (PLA2) is a novel anticancer polymer therapeutic. Dextrin conjugation decreases PLA2 bioactivity, but this can be restored following triggered degradation by α-amylase. The conjugate displays reduced hemolytic activity but retains, or shows enhanced, cytotoxicity in vitro that partially correlates with epidermal growth factor receptor (EGFR) expression. Here, we investigate further the mechanism of action of dextrin−PLA2 with the aim of judging its potential for combination with tyrosine kinase inhibitors (TKI) and/or chemotherapy and selecting the first models for in vivo evaluation. The endocytic fate of Oregon Green (OG)-labeled probes was assessed in MCF-7 cells. Whereas PLA2-OG showed greatest membrane binding, the dextrin−PLA2-OG conjugate displayed higher internalization. Moreover, cells incubated with PLA2-OG and dextrin−PLA2-OG showed an altered pattern of intracellular vesicle distribution compared to dextrin−OG. When cell lines known to express different levels of EGFR were used to assess cytotoxicity, free PLA2 activity was enhanced by addition of EGF whereas the conjugate was less cytotoxic, perhaps due to differences in their PK/PD profile. Co-incubation of cells with the TKI inhibitor, gefitinib, led to reduced cytotoxicity of both PLA2 and dextrin−PLA2 suggesting a TK-mediated PLA2 mechanism of action. However, the enhanced cytotoxicity seen in the presence of doxorubicin suggested potential for development of a dextrin−PLA2/doxorubicin combination therapy.
| Item Type: | Article |
|---|---|
| Additional Information: | [1] Publication Date (Web): February 17, 2010. Published in Molecular Pharmaceutics, 7(2), April 05, 2010. |
| Uncontrolled Keywords: | polymer therapeutics, cancer, PLA2, dextrin, anticancer conjugates, nanomedicines, PUMPT |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology |
| Faculty / School / Research Centre / Research Group: | Faculty of Engineering & Science > School of Science (SCI) |
| Related URLs: | |
| Last Modified: | 06 Nov 2020 11:23 |
| URI: | http://gala.gre.ac.uk/id/eprint/3532 |
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