Vitamins as potent cancer treatments through regulating the activity and expression of MMP ‐2 and MMP ‐9

Matrix metalloproteinases (MMP‐2 and MMP‐9) are key regulators of cancer progression, contributing to tumor invasion, angiogenesis, and metastasis. Despite the development of synthetic inhibitors, their clinical application remains limited due to toxicity and safety concerns. In this study, we investigated the potential of common vitamins, vitamin A (VA), vitamin B 6 (VB), vitamin C (VC), and vitamin D 3 (VD), as regulators of MMP‐2/9 expression and activity in lung (A549) and cervical (HeLa) cancer cells. Immunofluorescence and Western blot analyses revealed that all examined vitamins could reduce MMP‐2 and MMP‐9 expression, with VA, VD, and VB exhibiting pronounced inhibitory effects in both cell lines. VC showed comparatively modest effects, particularly on MMP‐2 expression. Mechanistically, these reductions were associated with the suppression of MAPK signaling pathways, including decreased phosphorylation of JNK and ERK. Enzymatic activity assays demonstrated that VA and VD selectively inhibited MMP‐2 activity in a dose‐dependent manner, whereas no significant inhibition of MMP‐9 activity was observed. Docking simulations suggested that VA could interact with the S1′ pocket of MMP‐2, while VD could bind near the catalytic domain, supporting their inhibitory potential. Collectively, these findings indicate that vitamins, particularly VA, VD, and VB, could regulate both MMP‐2 and MMP‐9 expression and activity through transcriptional and MAPK signaling pathway modulation. This study highlights the potential of vitamins as low‐toxicity therapeutic or adjunct agents for targeting MMP‐mediated cancer progression.