Characterization of carfilzomib-resistant non-small cell lung cancer cell lines

Journal of Cancer Research and Clinical Oncology
Neale T HankeAmanda F Baker

Abstract

We previously showed that carfilzomib (CFZ) has potent anti-proliferative and cytotoxic activity in a broad range of lung cancer cell lines. Here we investigate possible mechanisms of CFZ acquired resistance in lung cancer cell lines. CFZ-resistant non-small cell lung cancer (NSCLC) cell lines were developed by exposing A549 and H520 cells to stepwise increasing concentrations of CFZ. Resistance to CFZ and cross-resistance to bortezomib and other chemotherapy drugs was measured using the MTT assay. Cytotoxicity to CFZ was determined using a CytoTox assay. Western blot was used to measure apoptosis, autophagy, and drug efflux transporter-related proteins. Quantitative targeted whole transcriptome sequencing and quantitative RT-PCR was used to measure gene expression. Flow cytometry was used to analyze intracellular accumulation of doxorubicin. The CFZ IC50 value of the resistant cells increased versus parental lines (2.5-fold for A549, 122-fold for H520). Resistant lines showed reduced expression of apoptosis and autophagy markers and reduced death versus parental lines following CFZ treatment. Both resistant lines exhibited higher P-glycoprotein (Pgp) gene (TempO-Seq® analysis, increased 1.2-fold in A549, > 9000-fold in H520) a...Continue Reading

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Citations

Aug 25, 2019·International Journal of Molecular Sciences·Qingbin CuiZhe-Sheng Chen
Jul 14, 2020·Frontiers in Genetics·Pierre R BushelScott S Auerbach
Jul 27, 2021·Journal of Medicinal Chemistry·Min Jae LeeKyung Bo Kim

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