6-aminonicotinamide dismantles proliferative and migratory capacities of oral cancer cells via PPP blockade.
OBJECTIVE Cancer cells frequently exploit the Pentose Phosphate Pathway (PPP) to fuel antioxidant defenses and the synthesis of essential biomolecular precursors. It is hypothesized that sustained upregulation of glucose flux through the PPP is crucial for meeting the anabolic demands of cancer cells and mitigating oxidative stress. We investigated whether pharmacological inhibition of the rate-limiting PPP enzyme, glucose 6-phosphate dehydrogenase (G6PD), could decrease proliferation, disrupt cell-cell interactions, and impede migration in oral squamous cell carcinoma (OSCC). DESIGN Non-tumorigenic keratinocytes (HaCaT), less invasive (CAL27) and highly invasive (SCC9) OSCC had the G6PD pathway inhibited using 6-aminonicotinamide (6-AN) and then submitted to proliferation, spheroid formation, and cell migration assays. RESULTS Inhibition of G6PD significantly decreased cell proliferation, disrupted spheroid integrity, and reduced migratory capacity across both OSCC cell lines, while exhibiting only moderate cytotoxicity towards non-tumorigenic keratinocytes, yielding Selectivity Index (SI) values of 1.47 for CAL27 and 3.39 for highly invasive SCC9 cells. CONCLUSION Given that cancer cells often detach and migrate within challenging microenvironments, the ability of 6-AN to induce metabolic stress and impede both cell-cell interactions and migration highlights its potential as an adjuvant therapeutic strategy against OSCC progression.