Optical Redox Imaging of Treatment Responses to Nampt Inhibition and Combination Therapy in Triple-Negative Breast Cancer Cells.

Allison Podsednik,Annemarie Jacob,Lin Z Li,He N Xu,Jinxia Jiang

doi:10.3390/ijms22115563

Allison Podsednik, Annemarie Jacob + Show 3 more

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https://doi.org/10.3390/ijms22115563

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Abstract

We evaluated the utility of optical redox imaging (ORI) to identify the therapeutic response of triple-negative breast cancers (TNBC) under various drug treatments. Cultured HCC1806 and MDA-MB-231 cells treated with FK866 (nicotinamide phosphoribosyltransferase (Nampt) inhibitor), FX11 (lactate dehydrogenase A inhibitor), paclitaxel, and their combinations were subjected to ORI, followed by imaging fluorescently labeled reactive oxygen species (ROS). Cell growth inhibition was measured by a cell viability assay. We found that both cell lines experienced significant NADH decrease and redox ratio (Fp/(NADH+Fp)) increase due to FK866 treatment; however, HCC1806 was much more responsive than MDA-MB-231. We further studied HCC1806 with the main findings: (i) nicotinamide riboside (NR) partially restored NADH in FK866-treated cells; (ii) FX11 induced an over 3-fold NADH increase in FK866 or FK866+NR pretreated cells; (iii) FK866 combined with paclitaxel caused synergistic increases in both Fp and the redox ratio; (iv) FK866 sensitized cells to paclitaxel treatments, which agrees with the redox changes detected by ORI; (v) Fp and the redox ratio positively correlated with cell growth inhibition; and (vi) Fp and NADH positively correlated with ROS level. Our study supports the utility of ORI for detecting the treatment responses of TNBC to Nampt inhibition and the sensitization effects on standard chemotherapeutics.

Highlights

Breast cancer is the most diagnosed cancer among women, with ~15% of breast cancer patients possessing a triple-negative breast cancer (TNBC) subtype, i.e., absence of estrogen and progesterone receptors (ER−, PR−), and lack of HER2 overexpression (HER2−) [1,2]
optical redox imaging (ORI) was applied to detect the response to 48 h FK866 treatment in two TNBC breast cancer cell lines, HCC1806 and MDA-MB-231
The present study found that the optical redox imaging technique readily detects the therapeutic effects of both single treatment of FK866 and paclitaxel and their combinations on TNBC cells

Summary

Introduction

Breast cancer is the most diagnosed cancer among women, with ~15% of breast cancer patients possessing a triple-negative breast cancer (TNBC) subtype, i.e., absence of estrogen and progesterone receptors (ER−, PR−), and lack of HER2 overexpression (HER2−) [1,2]. With current treatment options limited to surgery and systemic chemotherapy, TNBC has the worst prognosis among breast cancer molecular types TNBC is a highly heterogeneous group of breast cancers with diverse therapeutic responses to chemotherapy [3,4]. Sensitive and early biomarkers for response to chemotherapy are crucial for the determination of responders versus non-responders and optimization of cancer treatment strategies [5]. Metabolic changes at the molecular level precede morphological/pathological changes and are expected to provide early biomarkers for treatment response. Cancer metabolism provides new therapeutic targets that will potentially enhance treatment effects when combined with conventional chemotherapy. Suppression of Nampt expression has been found to reduce the viability of breast cancer cells and increase their susceptibility to chemotherapy [12,14]

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