Abstract
This study was designed to investigate whether proton pump inhibitors (PPI, V-ATPase blocker) could increase the effect of cytotoxic agents in chemoresistant epithelial ovarian cancer (EOC). Expression of V-ATPase protein was evaluated in patients with EOC using immunohistochemistry, and patient survival was compared based on expression of V-ATPase mRNA from a TCGA data set. In vitro, EOC cell lines were treated with chemotherapeutic agents with or without V-ATPase siRNA or PPI (omeprazole) pretreatment. Cell survival and apoptosis was assessed using MTT assay and ELISA, respectively. In vivo experiments were performed to confirm the synergistic effect with omeprazole and paclitaxel on tumor growth in orthotopic and patient-derived xenograft (PDX) mouse models. Expression of V-ATPase protein in ovarian cancer tissues was observed in 44 patients (44/59, 74.6%). Higher expression of V-ATPase mRNA was associated with poorer overall survival in TCGA data. Inhibition of V-ATPase by siRNA or omeprazole significantly increased cytotoxicity or apoptosis to paclitaxel in chemoresistant (HeyA8-MDR, SKOV3-TR) and clear cell carcinoma cells (ES-2, RMG-1), but not in chemosensitive cells (HeyA8, SKOV3ip1). Moreover, the combination of omeprazole and paclitaxel significantly decreased the total tumor weight compared with paclitaxel alone in a chemoresistant EOC animal model and a PDX model of clear cell carcinoma. However, this finding was not observed in chemosensitive EOC animal models. These results show that omeprazole pretreatment can increase the effect of chemotherapeutic agents in chemoresistant EOC and clear cell carcinoma via reduction of the acidic tumor microenvironment.
Highlights
Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecological cancers and the five-year survival rate is dismal at 11% for patients with stage IV and 23%–41% for patients with stage III EOC [1]
In order to test whether inhibition of V-ATPase could enhance chemosensitivity, EOC cell lines were transfected with V-ATPase specific Small interfering RNA (siRNA)
In examining epithelial ovarian cancer patients in a The Cancer Genome Atlas (TCGA) cohort, we found that higher expression of
Summary
Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecological cancers and the five-year survival rate is dismal at 11% for patients with stage IV and 23%–41% for patients with stage III EOC [1]. One of the major obstacles to overcoming this bleak prognosis is tumor chemoresistance that arises following treatment with taxane and platinum-based agents, which is the standard regimen of chemotherapy for post-surgery EOC [2]. Chemoresistance of cancer cells can occur by genetic or epigenetic mechanisms [3, 4] but the acidic tumor microenvironment has been shown to increase the chemoresistance of solid tumors [3]. Highdose proton pump inhibitors (PPI), which inhibit acidic microenvironments by blocking the activity of vacuolar H+-ATPases (V-ATPases), have been shown to enhance the effect of chemotherapeutic agents on chemoresistant tumors developed in companion animals [7]. This study was designed to investigate whether PPI increase the cytotoxic effect of chemotherapy in chemoresistant EOC cells in vitro and in vivo
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