Comparative Evaluation of Annonacin and 2-Deoxy-D-Glucose on Lung Adenocarcinoma and Normal Bronchial Cells: Differential Effects on Viability, Proliferation and Antioxidant Defense

Background/Objectives: Cancer cells exhibit metabolic reprogramming, enabling them to switch between glycolysis and oxidative phosphorylation for ATP generation necessary for survival, proliferation and metastasis. This adaptability allows cancer cells to evade conventional therapy options that target only one metabolic pathway among others and lead to cancer resurgence and treatment resistance. The goal of this investigation was to evaluate the dual inhibition of these metabolic pathways with Annonacin and 2-DG in individual and combination modalities on A549 and NL20 cells to develop selective therapies for cancer cells, sparing normal cells. This dual attack was hypothesized to improve treatment effectiveness with triggering of cancer cell death by exploiting the metabolic vulnerabilities, disrupting glucose metabolism, modulating oxidative stress and inducing apoptosis through generation of reactive oxygen species (ROS) mediated DNA damage. Methods: The [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]-MTT and clonogenic assays were employed to assess the viability and proliferation capacity, respectively in A549 cancer and NL20 normal cells exposed to individual and combination treatment of Annonacin and 2-DG. Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) assays were employed to evaluate treatment mediated oxidative stress. Results: The combination treatment showed enhanced cytotoxicity compared to individual application, while normal cells exhibited differential and selective response. Conclusions: These findings provided the preclinical evidence for the potential therapeutic application of Annonacin and 2-DG as a dual metabolic targeting strategy for NSCLC. Future in vitro and in vivo research are necessary to understand the underlying mechanisms in detail and potentially translate them into treatment against NSCLC.