Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis

Abstract

A dysregulation of the cell-death mechanism contributes to poor prognosis in lung cancer. New potent chemotherapeutic agents targeting apoptosis-deregulating molecules have been discovered. In this study, 22-(4-pyridinecarbonyl) jorunnamycin A (22-(4′py)-JA), a synthetic derivative of bistetrahydroisoquinolinequinone from the Thai blue sponge, was semisynthesized by the Steglich esterification method, and its pharmacological mechanism in non-small-cell lung cancer (NSCLC) was elucidated by a network pharmacology approach. All predicted targets of 22-(4′py)-JA and genes related to NSCLC were retrieved from drug-target and gene databases. A total of 78 core targets were identified, and their associations were analyzed by STRING and Cytoscape. Gene ontology and KEGG pathway enrichment analyses revealed that molecules in mitogen-activated protein kinase (MAPK) signaling were potential targets of 22-(4′py)-JA in the induction of NSCLC apoptosis. In silico molecular docking analysis displayed a possible interaction of ERK1/2 and MEK1 with 22-(4′py)-JA. In vitro anticancer activity showed that 22-(4′py)-JA has strong cytotoxic and apoptosis-inducing effects in H460, H292 and A549 NSCLC cells. Furthermore, immunoblotting confirmed that 22-(4′py)-JA induced apoptotic cell death in an ERK/MEK/Bcl-2-dependent manner. The present study demonstrated that 22-(4′py)-JA exhibited a potent anticancer effect that could be further developed for clinical application and showed that network pharmacology approaches are a powerful tool to illustrate the molecular pathways of new drugs or compounds.

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

“…The upregulation of these proteins is associated with increased invasiveness and angiogenesis in cancers. , Inhibition of AKT activity has been shown to result in the downregulation of MMP-2 and MMP-9, consequently impeding cancer cell metastasis. , Additionally, AKT inhibition has been reported to attenuate the EGFR-mediated increase in VEGF and the endothelial tube-forming process. , In the context of this study, 22-(4′-py)-JA exhibits molecular signaling in lung cancer metastasis through the AKT/mTOR mechanism, effectively inhibiting EGF-mediating AKT/mTOR activation. It is worth noting that there is a crosstalk between AKT and ERK signaling, and a recent study demonstrated that 22-(4′-py)-JA suppressed ERK activity, contributing to apoptosis induction . However, in the present study, the phosphorylated ERK level was unaffected by a low dose of 22-(4′-py)-JA in suppressing cancer invasion and angiogenesis.…”

“…exhibits a promising anticancer activity . Evidence from in vitro studies shows that 22-(4′-py)-JA induces apoptosis in multiple NSCLC cell lines via an ERK/Bcl-2-dependent mechanism . The present study explores an antimetastasis activity and elucidates its underlying molecular mechanism.…”

“…19 Evidence from in vitro studies shows that 22-(4′-py)-JA induces apoptosis in multiple NSCLC cell lines via an ERK/Bcl-2-dependent mechanism. 28 The present study explores an antimetastasis activity and elucidates its underlying molecular mechanism. The results indicate that 22-(4′-py)-JA effectively inhibits in vitro invasion and angiogenesis and in vivo metastasis through the AKT/mTOR pathway.…”

“…27 The incorporation of the 4′-pyridine carbonyl group at the C-22 position led to the formation of the 22-(4′-py)-JA derivative (Figure 1A), which displayed a strong cytotoxic activity relative to the other derivatives 27 and induced apoptosis through an ERK/Bcl-2-dependent mechanism. 28 However, the impact of 22-(4′-py)-JA on cancer metastasis remains unknown. The objective of this study was to evaluate the antimetastatic activity of 22-(4′-py)-JA, specifically its effect on the invasiveness and angiogenesis using in vitro NSCLC culture and in vivo metastasis model.…”

“…According to the structure of trabectedin, the incorporation of a 4′-pyridine carbonyl ester moiety remarkably led to the most substantial improvement in cytotoxic activity among all of the derivatives tested . The incorporation of the 4′-pyridine carbonyl group at the C-22 position led to the formation of the 22-(4′-py)-JA derivative (Figure A), which displayed a strong cytotoxic activity relative to the other derivatives and induced apoptosis through an ERK/Bcl-2-dependent mechanism . However, the impact of 22-(4′-py)-JA on cancer metastasis remains unknown.…”