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

Marissa Williams¹ 

[1] The Tumour Bank, Children’s Cancer Research Unit, the Children’s Hospital at Westmead, Westmead, NSW 2145, Australia; E-Mail

关键词: rhabdomyosarcoma;    sequestration;    membrane trafficking;    vesicles;    drug resistance;    co-inhibitors;   

DOI  :  10.3390/ijms140713042

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland