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 have potential for clinical use in the treatment of gemcitabine-resistant human pancreatic cancer.
Highlights
Gemcitabine is a drug of choice in the treatment of human pancreatic cancer
We have recently reported that several small-molecule naphthalene diimide d erivatives[25,26], notably the trisubstituted compound CM0327, are potent inhibitors of cancer cell growth, with CM03 (Fig. 1b) having a GI50 value of ca 11 nM in the Pancreatic ductal adenocarcinoma (PDAC) cell lines PANC-1 and MIA PaCa-2
Its validity as a resistant line is supported by the changes in expression for several genes associated with gemcitabine resistance, notably DCK, cytidine deaminase (CDA), GLI1 and ST6GAL1
Summary
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. 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 gemcitabineresistant line. The analysis has 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 have potential for clinical use in the treatment of gemcitabine-resistant human pancreatic cancer. RNA-seq methodology has shown that CM03 targets a number of genes involved with PDAC initiation and progression in these cell lines, and has significant anti-cancer activity in in vivo xenograft and genetic models for the disease. In the light of the results presented here, the role that CM03 and related compounds could play in the clinic for the treatment of drug resistant PDAC
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