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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 *
Received: 16 April 2013; in revised form: 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 which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

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.

AMA Style

Williams M, Catchpoole D. Sequestration of AS-DACA into Acidic Compartments of the Membrane Trafficking System as a Mechanism of Drug Resistance in Rhabdomyosarcoma. International Journal of Molecular Sciences. 2013; 14(7):13042-13062.

Chicago/Turabian Style

Williams, Marissa; Catchpoole, Daniel. 2013. "Sequestration of AS-DACA into Acidic Compartments of the Membrane Trafficking System as a Mechanism of Drug Resistance in Rhabdomyosarcoma." Int. J. Mol. Sci. 14, no. 7: 13042-13062.


Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert