Molecular Dissection of Induced Platinum Resistance through Functional and Gene Expression Analysis in a Cell Culture Model of Bladder Cancer

PloS One
Sisi WangPaul T Henderson

Abstract

We report herein the development, functional and molecular characterization of an isogenic, paired bladder cancer cell culture model system for studying platinum drug resistance. The 5637 human bladder cancer cell line was cultured over ten months with stepwise increases in oxaliplatin concentration to generate a drug resistant 5637R sub cell line. The MTT assay was used to measure the cytotoxicity of several bladder cancer drugs. Liquid scintillation counting allowed quantification of cellular drug uptake and efflux of radiolabeled oxaliplatin and carboplatin. The impact of intracellular drug inactivation was assessed by chemical modulation of glutathione levels. Oxaliplatin- and carboplatin-DNA adduct formation and repair was measured using accelerator mass spectrometry. Resistance factors including apoptosis, growth factor signaling and others were assessed with RNAseq of both cell lines and included confirmation of selected transcripts by RT-PCR. Oxaliplatin, carboplatin, cisplatin and gemcitabine were significantly less cytotoxic to 5637R cells compared to the 5637 cells. In contrast, doxorubicin, methotrexate and vinblastine had no cell line dependent difference in cytotoxicity. Upon exposure to therapeutically relevant d...Continue Reading

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Citations

Sep 23, 2016·Chemical Research in Toxicology·Tiffany M ScharadinPaul T Henderson
Oct 12, 2016·Chemical Research in Toxicology·Heather A EnrightKenneth W Turteltaub
Dec 13, 2016·Chemical Research in Toxicology·Alessia StornettaShana J Sturla
May 12, 2019·Toxics·Michael A MalfattiKenneth W Turteltaub
Oct 12, 2018·Scientific Reports·Nicholas R HumGabriela G Loots
Dec 30, 2017·Molecular Cancer Therapeutics·Fuli WangChong-Xian Pan
Dec 3, 2016·Molecular Cancer Therapeutics·Maike ZimmermannPaul T Henderson
Aug 29, 2018·Chemical Research in Toxicology·Tiffany M ScharadinBrian A Jonas
Nov 2, 2018·Chemical Research in Toxicology·Sisi WangPaul T Henderson
Nov 15, 2019·ACS Biomaterials Science & Engineering·Andrea MazzocchiShay Soker

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Datasets Mentioned

BETA
SRR1820076
SRR1820077
SRR1820079
SRR1820080

Methods Mentioned

BETA
Assay
PCR
RNA-Seq
RNA seq
RNAseq
xenografts

Software Mentioned

AMS
STAT
SAS
GeneMapper ID
CASAVA
MedCalc
Cufflinks
RNAseq
TopHat

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