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Int. J. Mol. Sci. 2013, 14(7), 13042-13062; doi:10.3390/ijms140713042
Article

Sequestration of AS-DACA into Acidic Compartments of the Membrane Trafficking System as a Mechanism of Drug Resistance in Rhabdomyosarcoma

 and
*
The Tumour Bank, Children's Cancer Research Unit, the Children's Hospital at Westmead, Westmead, NSW 2145, Australia
* Author to whom correspondence should be addressed.
Received: 16 April 2013 / Revised: 30 May 2013 / Accepted: 5 June 2013 / Published: 25 June 2013
(This article belongs to the Special Issue Regulation of Membrane Trafficking and Its Potential Implications)
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Abstract

The accumulation of weakly basic drugs into acidic organelles has recently been described as a contributor to resistance in childhood cancer rhabdomyosarcoma (RMS) cell lines with differential sensitivity to a novel topoisomerase II inhibitor, AS-DACA. The current study aims to explore the contribution of the endocytic pathway to AS-DACA sequestration in RMS cell lines. A 24-fold differential in AS-DACA cytotoxicity was detected between the RMS lines RD and Rh30. The effect of inhibitors of the endocytic pathway on AS-DACA sensitivity in RMS cell lines, coupled with the variations of endosomal marker expression, indicated the late endosomal/lysosomal compartment was implicated by confounding lines of evidence. Higher expression levels of Lysosomal-Associated Membrane Protein-1 (LAMP1) in the resistant RMS cell line, RD, provided correlations between the increased amount and activity of these compartments to AS-DACA resistance. The late endosomal inhibitor 3-methyladenine increased AS-DACA sensitivity solely in RD leading to the reduction of AS-DACA in membrane trafficking organelles. Acidification inhibitors did not produce an increase in AS-DACA sensitivity nor reduce its sequestration, indicating that the pH partitioning of weakly basic drugs into acidic compartments does not likely contribute to the AS-DACA sequestering resistance mechanism evident in RMS cells.
Keywords: rhabdomyosarcoma; sequestration; membrane trafficking; vesicles; drug resistance; co-inhibitors rhabdomyosarcoma; sequestration; membrane trafficking; vesicles; drug resistance; co-inhibitors
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Williams, M.; Catchpoole, D. Sequestration of AS-DACA into Acidic Compartments of the Membrane Trafficking System as a Mechanism of Drug Resistance in Rhabdomyosarcoma. Int. J. Mol. Sci. 2013, 14, 13042-13062.

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