Cancer drug resistance (CDR) is a central problem in therapeutic failure. Several mechanisms
can underlie CDR, including increased expression and activity of efflux ABC transporters and epigenetic
phenomena. A topic that is not usually addressed is the mechanism underlying the loss of resistance to
therapy once the challenge to these cells is withdrawn.
A KCR cell line (doxorubicin-resistant and expressing ABCB1) was used to induce loss of
resistance by withdrawing doxorubicin in culture medium, assess ABCB1 expression and activity and
determine a signature of microRNAs expression. The activity of ABCB1 was analysed by fluorescence
microscopy and flow cytometry through fluorescence (DiOC2) substrate retention assays. Expression
of 1008 microRNAs was assessed before and after doxorubicin withdrawal.
After 16 weeks of doxorubicin withdrawal we observed a decrease of ABCB1 activity and
expression. Moreover, we determined a signature of 23 microRNAs, 13 under-expressed and 10 over expressed, as a tool to assess loss of resistance. Through pathway enrichment analysis, “Pathways in
cancer”, “Proteoglycans in cancer” and “ECM-receptor interaction” were identified as relevant pathways
in loss of CDR.
Taken together, the data reported reinforces the assumption that ABCB1 may play a major role
in the kinetics of CDR and their levels of expression are in the dependence of the circuitry of cell miRNAs
