A G-quadruplex-binding compound shows potent activity in human gemcitabine-resistant pancreatic cancer cells.

Scientific Reports
Ahmed A AhmedStephen Neidle

Abstract

Gemcitabine is a drug of choice in the treatment of human pancreatic cancer. Chemo-resistance to this drug is common and has been attributed to a variety of distinct mechanisms, involving > 100 genes. A recently developed small-molecule G-quadruplex ligand, the trisubstituted naphthalene diimide compound CM03, has previously been shown to have equivalent potency to gemcitabine in the pancreatic cancer cell line MIA PaCa-2. We report here on cell lines of increased resistance to gemcitabine that have been generated from this line, with the most resistant having 1,000-fold reduced sensitivity to gemcitabine. These resistant lines retain nM sensitivity to CM03. The molecular basis for the retention of potency by this G-quadruplex ligand has been examined using whole transcriptome data analysis with RNA-seq. This has revealed that the pattern of pathways down regulated by CM03 in the parental MIA PaCa-2 cell line is largely unaffected in the gemcitabine-resistant line. The analysis has also shown that the expression patterns of numerous genes involved in gemcitabine sensitivity are down regulated in the resistant line upon CM03 treatment. These results are supportive of the concept that G-quadruplex small molecules such as CM03 hav...Continue Reading

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Citations

Nov 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Ahmed Abdullah Ahmed, Stephen Neidle
Mar 23, 2021·Journal of Medicinal Chemistry·Chiara PlatellaDaniela Montesarchio
May 23, 2021·Metallomics : Integrated Biometal Science·Samar AliSophie Bombard
Jul 3, 2021·Cancers·Victoria Sanchez-MartinJose Antonio Garcia-Salcedo
Jul 27, 2021·Journal of Cell Communication and Signaling·Amjesh RevikumarRajesh Raju

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Datasets Mentioned

BETA
GSE148200
GSE105083

Methods Mentioned

BETA
xenograft
RNA-seq
Chip
Assay
PCR

Software Mentioned

Trimmomatic
JE
Pathview maps
Suite
bcl2fastq Conversion
SARTools
DAVID
STAR
FeatureCounts
Illumina

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