Metabolic cofactors NAD(P)H and FAD as potential indicators of cancer cell response to chemotherapy with paclitaxel

• Published in: Biochimica et biophysica acta. General subjects Vol. 1862; no. 8; pp. 1693 - 1700
• Main Authors: Lukina, Maria M., Dudenkova, Varvara V., Ignatova, Nadezhda I., Druzhkova, Irina N., Shimolina, Lyubov' E., Zagaynova, Elena V., Shirmanova, Marina V.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2018
• Subjects: Antineoplastic Agents, Phytogenic; Apoptosis - drug effects; biomarkers; Biomarkers - metabolism; Cancer cell; cell death; Chemotherapy; drug therapy; drugs; Early response; Flavin-Adenine Dinucleotide - metabolism; fluorescence; Humans; Metabolic cofactors; Microscopy, Fluorescence, Multiphoton; monitoring; NADP (coenzyme); NADP - metabolism; neoplasm cells; neoplasms; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oxidation-Reduction; Paclitaxel; Paclitaxel - pharmacology; Tumor Cells, Cultured; Early response; FAD; FLIM; Chemotherapy; TCA; FBS; ROS; IC50; Metabolic cofactors; Paclitaxel; Cancer cell; PI; NAD(P)H
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2018.04.021

Paclitaxel, a widely used antimicrotubular agent, predominantly eliminates rapidly proliferating cancer cells, while slowly proliferating and quiescent cells can survive the treatment, which is one of the main reasons for tumor recurrence and non-responsiveness to the drug. To improve the efficacy of chemotherapy, biomarkers need to be developed to enable monitoring of tumor responses. In this study we considered the auto-fluorescent metabolic cofactors NAD(P)H and FAD as possible indicators of cancer cell response to therapy with paclitaxel. It was found that, among the tested parameters (the fluorescence intensity-based redox ratio FAD/NAD(P)H, and the fluorescence lifetimes of NAD(P)H and FAD), the fluorescence lifetime of NAD(P)H is the most sensitive in tracking the drug response, and is capable of indicating heterogeneous cellular responses both in cell monolayers and in multicellular tumor spheroids. We observed that metabolic reorganization to a more oxidative state preceded the morphological manifestation of cell death and developed faster in cells that were more responsive to the drug. Our results suggest that noninvasive, label-free monitoring of the drug-induced metabolic changes by noting the NAD(P)H fluorescence lifetime is a valuable approach to characterize the responses of cancer cells to anti-cancer treatments and, therefore, to predict the effectiveness of chemotherapy. •FLIM of NAD(P)H enables the visualization of cellular metabolic heterogeneity and early responses to paclitaxel;•Faster reorganization from the glycolytic toward a more oxidative state is detected in more responsive cells;•Rapidly proliferating cells with an accelerated glycolytic metabolism display greater changes in NAD(P)H fluorescence.