Screening for phenotype selective activity in multidrug resistant cells identifies a novel tubulin active agent insensitive to common forms of ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-12

AUTHORS

Mårten Fryknäs, Joachim Gullbo, Xin Wang, Linda Rickardson, Malin Jarvius, Malin Wickström, Saadia Hassan, Claes Andersson, Mats Gustafsson, Gunnar Westman, Peter Nygren, Stig Linder, Rolf Larsson

ABSTRACT

BACKGROUND: Drug resistance is a common cause of treatment failure in cancer patients and encompasses a multitude of different mechanisms. The aim of the present study was to identify drugs effective on multidrug resistant cells. METHODS: The RPMI 8226 myeloma cell line and its multidrug resistant subline 8226/Dox40 was screened for cytotoxicity in response to 3,000 chemically diverse compounds using a fluorometric cytotoxicity assay (FMCA). Follow-up profiling was subsequently performed using various cellular and biochemical assays. RESULTS: One compound, designated VLX40, demonstrated a higher activity against 8226/Dox40 cells compared to its parental counterpart. VLX40 induced delayed cell death with apoptotic features. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. Strong connections to tubulin inhibitors and microtubule cytoskeleton were retrieved. The mechanistic hypothesis of VLX40 acting as a tubulin inhibitor was confirmed by direct measurements of interaction with tubulin polymerization using a biochemical assay and supported by demonstration of G2/M cell cycle arrest. When tested against a broad panel of primary cultures of patient tumor cells (PCPTC) representing different forms of leukemia and solid tumors, VLX40 displayed high activity against both myeloid and lymphoid leukemias in contrast to the reference compound vincristine to which myeloid blast cells are often insensitive. Significant in vivo activity was confirmed in myeloid U-937 cells implanted subcutaneously in mice using the hollow fiber model. CONCLUSIONS: The results indicate that VLX40 may be a useful prototype for development of novel tubulin active agents that are insensitive to common mechanisms of cancer drug resistance. More... »

PAGES

374

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1471-2407-13-374

DOI

http://dx.doi.org/10.1186/1471-2407-13-374

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1022530542

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23919498


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