Targeting Microtubule-Associated Protein Tau in Chemotherapy-Resistant Models of High-Grade Serous Ovarian Carcinoma.

Abstract

Simple SummaryResistance to chemotherapy in patients with high-grade serous ovarian carcinoma is a clinically relevant problem, and it results in high mortality. The aim of the study was to determine whether targeting microtubule-associated protein tau could reduce cell proliferation and tumor burden in cell culture and mouse models of chemotherapy-resistant high-grade serous ovarian carcinoma. To achieve this aim, I tested an inhibitor of tau, leucomethylene blue, which was originally developed against neurodegenerative diseases, and found that it efficiently reduced cell and tumor growth. Additionally, paclitaxel and leucomethylene blue synergized in reducing cell growth and tumor burden. Altogether, the data demonstrate that tau could be considered a new target for treatment of chemotherapy-resistant high-grade serous ovarian carcinoma, and leucomethylene blue could potentially add to the arsenal of drugs to treat the terminal stage of this deadly malignancy.Relapsed, recurrent, chemotherapy-resistant high-grade serous ovarian carcinoma is the deadliest stage of this disease. Expression of microtubule-associated protein tau (tau) has been linked to resistance to paclitaxel treatment. Here, I used models of platinum-resistant and created models of platinum/paclitaxel-resistant high-grade serous ovarian carcinoma to examine the impact of reducing tau expression on cell survival and tumor burden in cell culture and xenograft and syngeneic models of the disease. Tau was overexpressed in platinum/paclitaxel-resistant models; expression of phosphoSer396 and phosphoThr181 species was also found. A treatment with leucomethylene blue reduced the levels of tau in treated cells, was cytotoxic in cell cultures, and efficiently reduced the tumor burden in xenograft models. Furthermore, a combination of leucomethylene blue and paclitaxel synergized in eliminating cancer cells in cell culture and xenograft models. These findings underscore the feasibility of targeting tau as a treatment option in terminal-stage high-grade serous ovarian cancer.