Investigating the Potential of NHE1 Inhibitors as Potential Adjuvant Therapies in the Treatment of Ovarian Cancer

Abstract

Each year in the United States over 200,000 women are diagnosed with ovarian cancer leading to more than 14,000 deaths. Increases in the expression and activity Na+‐H+ Exchanger Isoform 1 (NHE1) was recently demonstrated to regulate cell proliferation in ovarian cancer patients. NHE1 is an 815 amino acid transmembrane transport protein that regulates intracellular pH. NHE1 is hyperactivated in an array of cancer types leading to a pH inversion that supports both cell proliferation and invasion. One mechanism for this NHE1 hyperactivation is phosphorylation of the regulatory domain by a range of protein kinases. A significant issue in ovarian cancer therapy is the development of drug resistance and disease recurrence. In an effort to combat these outcomes, it is hypothesized that combining common ovarian cancer therapeutic agents along with compounds that indirectly inhibit NHE1 activation will enhance the ability of the therapeutic agents to slow ovarian cancer progression. Two ovarian adenocarcinoma cell lines; CAOV‐3 and SKOV‐3 are used in this research. Utilizing a proliferation assay, I assessed the impact of different ovarian cancer therapeutics, Rucaparib, Olaparib, Carboplatin and Cisplatin, in these two cell lines in the presence and absence of inhibitors that decrease NHE1 activity directly. This work has also been expanded to a three‐dimensional environment, investigating the impact of these combination therapies in a spheroid assay. To begin to evaluate mechanisms of NHE1 involvement changes, a steady‐state intracellular pH was measured. It is believed that through the pairing of chemotherapeutics with the NHE1 inhibitors, a synergistic effect will ensue in which the combination is more proficient at reducing cancer growth than either compound can alone. This relationship would allow for a reduction in the required drug dosage and harmful side effects in patients. These data indicate that the direct inhibition of NHE1 may serve as a potential therapeutic target in Ovarian Cancer treatment.