Bicarbonate-free pH neutralization resensitizes ovarian cancer to chemotherapy and is tracked by 3T CEST MRI

Abstract

Ovarian tumors that initially respond to platinum-taxane chemotherapy often relapse as chemoresistant disease. The acidic tumor microenvironment is a well-known but under-exploited driver of this resistance, and neutralization strategies such as oral bicarbonate have not translated. Here we show that inhibiting specific tumor pH regulators at noncytotoxic doses relieves acidosis and restores frontline chemotherapy, monitored noninvasively at clinical 3T. In OVCAR3 and SKOV-3 ovarian cancer cells, MCT1 and MCT4 were overexpressed under acidosis, and the MCT4 inhibitor acriflavine reduced extracellular acidification at concentrations well below its cytotoxic IC50, without bicarbonate buffering. Acidosis blunted the efficacy of both paclitaxel and carboplatin, raising their IC50 values, which acriflavine reversed. In SKOV-3 tumors, acidoCEST MRI with iopromide noninvasively measured baseline tumor acidosis and its normalization following acriflavine treatment. These results establish tumor acidosis as an imageable, druggable determinant of chemoresistance and a bicarbonate-free therapeutic target.