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

Abstract

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.

Natural Products Derived from Marine Sponges with Antitumor Potential against Lung Cancer: A Systematic Review

“…22-(4′-pyridinecarbonyl) jorunnamycin A (22-(4′-py)-JA) ( 4 ) is a synthetic derivative of jorunnamycin A ( 3 ) isolated from Xestospongia sp. [ 16 , 17 ]. This compound demonstrated robust cytotoxic efficacy in the nanomolar range, exerting an apoptosis-inducing effect on H460, H292, and A549 NSCLC cell lines through an ERK/MEK/Bcl-2-dependent mechanism [ 16 ].…”

“…In vitro assays demonstrated that inhibition of AKT/mTOR/P70S6K signaling pathway by 22-(4′-py)-JA resulted in the attenuation of matrix metalloproteinases (MMP-2 and MMP-9), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF). In vivo assays involving intravenous inoculation of the A549 cell line in mice revealed that the group treated with 22-(4′-py)-JA ( 4 ) exhibited a reduction in pulmonary nodules, thereby mitigating the metastatic progression [ 17 ]. Cell invasion and angiogenesis processes are related to the spread of tumor cells, leading to metastasis.…”

“…Among all the compounds belonging to Haplosclerida order, renieramycin M ( 1 ) and the derivatives of jorunnamycin A ( 4 ) and hydroquinone 5-O-monoester ( 2 ) stand out for their high antitumor activity against NSCLC lines H292 and H460, obtaining the lowest IC 50 [ 11 , 12 ]. In addition, the derivatives of compound 4 have been the only ones within this order that have been tested in in vivo assays with mice, obtaining interesting antimetastatic effects through the deregulation of the expression of metalloproteases and signaling pathways of this phenomenon (HIF and VEGF) [ 17 ]. Notably, they all belong to the alkaloid family.…”

“… Reduction of in vivo metastasis. [ 17 ] Xestospongia testudinaria langcosterol A ( 8 ), xestosterol ( 9 ), and 24-hydroperoxy-24-vinyl cholesterol ( 10 ) Sterol Isolation A549 (NSCLC) and WI-38 (NT) 8 : 63.1 and 68 9 : >100 and >100 10 : 29 and 43.4 IC 50 (μM) A549 and WI-38, respectively (72 h) ✗ NR [ 20 ] Cribrochalina vasculum (3S)-icos-4E-en-1-yn-3-ol ( 11 ) and (3S)-14-methyldocos-4E-en-1-yn-3-ol ( 12 ) Acetylenic alcohol Isolation U-1810 (NSCLC), U-1285, H69, H82 (SCLC), WI-38, and BEAS-2B (NT) 11 : 0.5, 1.6, 2.2, 1.1, 7.3, and 12.9 12 : 0.8, 1.8, 1.1, 1.1, 9.7, and N/A IC 50 (μM) U-1810, U-1285, H69, H82, WI-38, and BEAS-2B, respectively (72 h) ✗ Induction of apoptosis involving cleavage of caspase-9, caspase3, and PARP. Conformational changes in Bak and Bax and loss of mitochondrial potential and cytochrome release.…”

“…Conversely, other compounds such as (−)-petrosynoic acids ( 17 – 20 ) and pellynols ( 21 – 25 ) [ 26 ] or merosesquiterpenes ( 29 – 43 ) [ 38 ] showed no differences in the cytotoxic effect even a lower IC 50 in non-tumor lines compared to tumor cell lines. On the other hand, among the publications that include in vivo tests, only one of them includes data on the toxicity of peloruside A ( 53 ), indicating the maximum dose tolerated by mice [ 49 ], and other authors determine the pharmacokinetic parameters of 22-(4′-py)-JA ( 4 ) [ 17 ].…”