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A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second leading cause of cancer mortality by 2030. PDAC remains resistant to the majority of systemic chemotherapies. In this paper, we explore if epigenetic sensitization can improve chemotherapy response in PDAC. Multiple PDAC cell lines were tested with serial concentrations of the epigenetic modulators 5-azacitidine (Aza) and guadecitabine (SGI-110). Guadecitabine was effective at inhibiting the expression of DNA Methyltransferase 1 (DNMT1) and in decreasing cell viability at nanomolar concentrations. We also report that guadecitabine has increased efficacy following a delay period or as we reference, a 'rest period'. Sensitization with guadecitabine improved response to the chemotherapeutic agent-Irinotecan- as measured by decreased cell viability and accompanied by an increase in caspase activity. Additional studies are needed to understand the mechanism of action.

SUBMITTER: Thakar M

PROVIDER: S-EPMC6013229 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent.

Thakar Manjusha M Hu Yue Y Morreale Michael M Lerner Lane L Ying Lin Wan W Sen Rupashree R Cai Yi Y Karunasena Enusha E Thakar Maya M Saggi Soren S Keer Harold H Ahuja Nita N

PloS one 20180621 6

Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second leading cause of cancer mortality by 2030. PDAC remains resistant to the majority of systemic chemotherapies. In this paper, we explore if epigenetic sensitization can improve chemotherapy response in PDAC. Multiple PDAC cell lines were tested with serial concentrations of the epigenetic modulators 5-azacitidine (Aza) and guadecitabine (SGI-110). Guadecitabine was effective at inhibiting the expression of DNA Methyltransferase ...[more]

PMID: 29927979

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Project description:Simple Summary Muscle-invasive urothelial carcinoma of the bladder (UC) is treated with chemotherapies based on the DNA-damaging drug cisplatin, which only works temporarily due to the development of drug resistance. In this study, we show that it may be possible to overcome such resistances by treating the cancer cells with specific epigenetic drugs. We investigated the “epidrug” PLX51107 that inhibits the chromatin regulator BRD4 (Bromodomain Containing 4). PLX51107 inhibited cell growth, caused DNA damage, and blocked DNA repair response in UC cells. Concomitant application of PLX51107 with cisplatin or the drug talazoparib, interfering with DNA repair, caused cell death very efficiently. PLX51107 thus sensitizes UC cells to other drugs and may allow therapy with novel effective anti-tumor drugs like talazoparib that normally only work in a small proportion of patients with specific gene mutations. These results may help to improve current standard therapy and to develop new treatment options urgently required for UC patients. Abstract Muscle-invasive urothelial carcinoma (UC) is treated with cisplatin-based chemotherapy, which is only moderately efficient, mostly due to development of resistance. New therapy approaches are therefore urgently needed. Epigenetic alterations due to frequent mutations in epigenetic regulators contribute to development of the disease and to treatment resistance, and provide targets for novel drug combination therapies. Here, we determined the cytotoxic impact of the second-generation bromodomain protein inhibitor (BETi) PLX51107 on UC cell lines (UCC) and normal HBLAK control cells. PLX51107 inhibited proliferation, induced apoptosis, and acted synergistically with the histone deacetylase inhibitor romidepsin. While PLX51107 caused significant DNA damage, DNA damage signaling and DNA repair were impeded, a state defined as BRCAness. Accordingly, the drug strongly synergized with cisplatin more efficiently than romidepsin, and with the PARP inhibitor talazoparib to inhibit proliferation and induce cell death in UCC. Thus, a BETi can be used to “episensitize” UC cells to cytotoxic chemotherapy and inhibitors of DNA repair by inducing BRCAness in non BRCA1/2 mutated cancers. In clinical applications, the synergy between PLX51107 and other drugs should permit significant dosage reductions to minimize effects on normal tissues.

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A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent.

Publications

A novel epigenetic modulating agent sensitizes pancreatic cells to a chemotherapy agent.

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