Investigation of exercise-mimetic bioactive molecules as modulators of MMP activity and expression in cancer cells

Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, are directly involved in the degradation of the extracellular matrix preceding uncontrolled cancer growth and metastasis. For these reasons, MMPs are considered key therapeutic targets in the development of cancer treatments. Acknowledged for its prophylactic effects against various diseases including cancer, physical exercise has been reported to boost the immune system, enhance endogenous defence mechanisms, manage oxidative stress, and regulate MMP. Despite its benefits, patients with compromised capacity for physical activity due to injuries and frailty are often unable to take advantage of them. As a possible solution for this problem, the alternative therapeutic approach of exercise mimetics has been gaining traction through pharmacological interventions. Exercise mimetics are pharmacological agents that partially mimic the molecular and physiological benefits of physical exercise without requiring actual physical activity. Recent studies have indicated that the potential of these compounds may serve as candidates for further investigation in cancer treatment. In this study, the possible anti-cancer and anti-metastatic-related effects of six selected exercise mimetics (i.e., AICAR, Icariin, Berberine, Betaine, GW501516, and Metformin) were investigated by targeting activity and/or expression of MMP-2/9 in in vitro model. These compounds (i) inhibited MMP-2 activity by interacting with the active site and/or allosteric sites, (ii) downregulated MMP-2/9 expression by influencing STAT3 signalling pathways, and (iii) reduced lung cancer cells (A549) viability to varying degrees. Among the exercise mimetics, Icariin and Berberine have relatively stronger effects on both the activity of MMP-2 and the expression of MMP-2/9 in cancer cells. These findings highlight the novel potential of exercise mimetics as targeted cancer therapeutics through the regulation of MMP activity and expression in cancer progression and metastasis.