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rRNA disruption: a predictive marker of response to taxane chemotherapy
No full textA recent clinical trial for locally advanced breast cancer patients treated with epirubicin
and docetaxel prior to surgery reported significant dose-dependent reductions in tumour RNA
integrity values which correlated with pathological complete response. The purpose of the
present study was to assess whether similar chemotherapy-dependent alterations in RNA
integrity could occur in vitro and to assess its relationship, if any, to apoptosis. Treatment of
wildtype A2780 ovarian carcinoma cells with taxanes resulted in dose- and time-dependent RNA
degradation, identified as several unique bands on electropherograms having mobilities lower
than the 28S and 18S rRNAs. We refer to this chemotherapy-dependent generation of aberrant
RNA bands on electropherograms as “RNA disruption”. RNA disruption was found to be
temporally associated with the induction of apoptosis, as determined by the appearance of a sub
G1 peak of DNA content, positive annexin-V staining, and both PARP-1 and caspase-3 cleavage.
Treatment of cells with a caspase-3 inhibitor resulted in a significant reduction in rRNA
disruption, suggesting the involvement of caspase-3 or related caspases in RNA disruption. In
contrast, docetaxel-dependent rRNA disruption was absent when docetaxel was administered to
docetaxel-resistant A2780DXL cells, indicating that changes in RNA integrity may possibly
differentiate between responsive and non-responsive tumours in cancer patients
