Multidrug resistant non-small cell lung cancer cells exhibiting collateral sensitivity to DNA damaging drugs

AIM: Multidrug resistance (MDR) severely limits the efficacy of non-small lung cancer (NSCLC) treatment. Counteracting MDR is very difficult but highly necessary to extend the survival of MDR patients. This work aimed at establishing MDR NSCLC cellular models, to identify mechanisms responsible for their resistance to several treatments and new collateral sensitivity approaches to overcome MDR. METHODS: Two paclitaxel resistant cell sublines (A549-CDR1 and A549-CDR2) were established, by treating A549 cells with increasing concentrations of paclitaxel. The proteomic profile (liquid chromatography-mass spectrometry) of these sublines was assessed as well as their MDR phenotype by evaluating response to several chemotherapeutic drugs (Sulforhodamine B assay) and the expression levels (Western Blotting) and activity (Rhodamine-123 accumulation assay) of ATP-binding cassette (ABC) transporter proteins. Cell death, reactive oxygen species (ROS) production (flow cytometry) and DNA damage levels (Comet assay and Western Blotting) were also evaluated prior to and following treatments with several drugs. KEY FINDINGS: The two established paclitaxel resistant cell sublines exhibited distinct proteomic profiles, although both presented a MDR phenotype, confirmed by cross-resistance to other chemotherapeutic drugs and increased expression levels and activity of ABC transporter proteins. They presented lower proliferation, higher ROS levels and increased DNA damage levels. These MDR cells were more sensitive than their parental cells to DNA damaging drugs that are not P-glycoprotein (P-gp) substrates, thus presenting collateral sensitivity to such drugs. SIGNIFICANCE: The established NSCLC MDR cell lines are promising models to understanding mechanisms associated with MDR and exploiting collateral sensitivity approaches to overcome MDR in NSCLC.