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Increasing the therapeutic efficacy of docetaxel for cutaneous squamous cell carcinoma through the combined inhibition of phosphatidylinositol 3-kinase/AKT signalling and autophagy

Lookup NU author(s): Professor Mark Birch-Machin, Dr Robert Ellis, Dr Jane Renwick, Professor Penny Lovat

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Abstract

Early-stage cutaneous squamous cell carcinoma (cSCC) has a favourable prognosis. Metastatic disease is probably associated with chemoresistance mediated through the activation of pro-survival phosphatidylinositol 3-kinase/AKT signalling. Inhibition of activated AKT partially increases chemosensitivity but induces autophagy, the principal lysosomal mechanism for the bulk degradation and recycling of proteins and damaged organelles. The aim of the current study was to test the hypothesis that combined inhibition of AKT signalling and autophagy by the lysosomal inhibitor chloroquine increases the susceptibility to docetaxel-induced apoptosis of cSCC cells isolated from a lymph-node metastasis. Combined AKT inhibition and chloroquine treatment of MET 4 cSCC cells resulted in significantly enhanced inhibition of cell viability and apoptosis induced by clinically achievable concentrations of docetaxel (P<0.001). Inhibition of both autophagy and AKT thus represents an effective and viable therapeutic strategy to increase the cytotoxicity of docetaxel for the treatment of advanced cSCC.


Publication metadata

Author(s): Wright TJ, McKee C, Birch-Machin MA, Ellis R, Armstrong JL, Lovat PE

Publication type: Article

Publication status: Published

Journal: Clinical and Experimental Dermatology

Year: 2013

Volume: 38

Issue: 4

Pages: 421-423

Print publication date: 01/06/2013

Online publication date: 27/03/2013

Acceptance date: 15/01/2013

ISSN (print): 0307-6938

ISSN (electronic): 1365-2230

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1111/ced.12138

DOI: 10.1111/ced.12138


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