Epigenetic Treatment of Urothelial Carcinoma Cells Sensitizes to Cisplatin Chemotherapy and PARP Inhibitor Treatment

摘要

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” {"type":"entrez-protein","attrs":{"text":"PLX51107","term_id":"1321741095","term_text":"PLX51107"}}PLX51107 that inhibits the chromatin regulator BRD4 (Bromodomain Containing 4). {"type":"entrez-protein","attrs":{"text":"PLX51107","term_id":"1321741095","term_text":"PLX51107"}}PLX51107 inhibited cell growth, caused DNA damage, and blocked DNA repair response in UC cells. Concomitant application of {"type":"entrez-protein","attrs":{"text":"PLX51107","term_id":"1321741095","term_text":"PLX51107"}}PLX51107 with cisplatin or the drug talazoparib, interfering with DNA repair, caused cell death very efficiently. {"type":"entrez-protein","attrs":{"text":"PLX51107","term_id":"1321741095","term_text":"PLX51107"}}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.