Preclinical Characterization of 22-(4′-Pyridinecarbonyl) Jorunnamycin A against Lung Cancer Cell Invasion and Angiogenesis via AKT/mTOR Signaling

Non-small-cell lung cancer (NSCLC), the most prevalent form of lung cancer, is associated with an unfavorable prognosis owing to its high rate of metastasis. Thus, the identification of new drugs with potent anticancer activities is essential to improve the clinical outcome of this disease. Marine organisms exhibit a diverse source of biologically active compounds with anticancer effects. The anticancer effects of jorunnamycin A (JA) derived from the Thai blue sponge (Xestospongia sp.) and 22-(4'-pyridinecarbonyl) jorunnamycin A (22-(4'-py)-JA), the semisynthetic derivative of JA, have been reported. The present study aimed to investigate the impact of 22-(4'-py)-JA on NSCLC metastasis using in vitro, in vivo, and in silico approaches. The JA derivative inhibited tumor cell invasion and tube formation in human umbilical vein endothelial cells (HUVECs). The computational analysis demonstrated strong and stable interactions between 22-(4'-py)-JA and the AKT protein. Further examinations into the molecular mechanisms revealed the suppression of AKT/mTOR/p70S6K signaling by 22-(4'-py)-JA, leading to the downregulation of matrix metalloproteinases (MMP-2 and MMP-9), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF). Furthermore, 22-(4'-py)-JA suppressed in vivo metastasis by decreasing the number of colonies in the lung. These findings indicated the antimetastasis activity of 22-(4'-py)-JA, which might prove useful for further clinical applications.