The pentose phosphate pathway (PPP) is the most common pathway in most
cancer cells and stimulates
antioxidant defense mechanisms and synthesis of biomolecule precursors. It is believed that
cancer cells persistently ameliorate
glucose flux into the PPP to maintain their anabolic requirements and adjust oxidative stress. TCGA analyses have indicated the upregulation of
enzymes involved in PPP in
lung cancer. Hence, the present study aimed to determine whether the pharmacological blockade of
glucose 6-phosphate
dehydrogenase (G6PD), the primary and rate-limiting
enzyme involved in PPP, using
6-aminonicotinamide (6-AN), could induce antiproliferative activity in two
lung cancer cell lines. Exposure to 6-AN suppressed
lactate production and
glucose consumption, modified the mitochondrial potential and redox balance, and thereby induced the endoplasmic reticulum (ER) stress to reduce
lung cancer cell proliferation and govern cellular apoptosis. Collectively, this is the first study in which PPP blockade by 6-AN causes
reactive oxygen species (ROS)-mediated apoptosis by ER stress in
lung cancer cells. Further preclinical studies will be conducted to validate the biological applicability of these findings.