Can Less Be More: Evaluating the Synergistic Relationship between Chemotherapy Agents and NHE1 Inhibitors in Ovarian Cancer Cells

Abstract

Ovarian cancer is the seventh most prevalent cancer found in women, resulting in over 200,000 new cases and close to 140,000 deaths annually. In order to combat the risk of mortality associated with this disease, extensive chemotherapy regimes are employed. These measures often include the use of therapeutic agents such as paclitaxel, rucaparib, olaparib, and cisplatin. The mechanisms of action for each of these oncogenic therapeutics differs substantially. Paclitaxel stabilizes microtubule polymerization, effectively preventing mitotic completion. Rucaparib and olaparib both inhibit PARP, an enzyme associated with repairing damaged DNA. Cisplatin also hinders DNA repair. However, it does so by crosslinking the purine bases on DNA to promote cellular apoptosis. Although the use of such chemotherapy agents has been instrumental in reducing cancer‐related deaths, the dosage intensity of these cytostatics can procure adverse side effects in the form of hair loss, anemia, nausea, and vomiting. Because of this reality, it has become of interest to investigate methodologies for reducing the required chemotherapy drug dosage, while still maintaining the same rate of cancer cell death. The Na+‐H+ Exchanger Isoform 1 (NHE1) is a plasma membrane protein that exchanges 1 extracellular Na+ for 1 intracellular H+, thus playing a primary role in pH regulation. It is hypothesized that such a synergistic effect can be produced through the pairing of chemotherapy agents with NHE1 inhibitors. In cancer cells, NHE1 is often hyperactivated leading to the development of a pH inversion. This dysregulation contributes to increased cancer cell proliferation, migration and invasion. Inhibition of this transport protein typically results in intracellular acidification, a mechanism that supports the progression of apoptosis. Applying this inhibition, with an accompanying cytostatic, has thus interested researchers as a possible therapeutic approach towards mitigating neoplastic development. The potential of these drug‐inhibitor pairs will be measured primarily via flow cytometry. Through the addition of a fluorescent dye, this instrument is able to differentiate viable cells from compromised cells within a single population. Such analysis allows for a quantitative assessment of each inhibitor‐drug combination.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.