Aaptamine attenuates the proliferation and progression of non-small cell lung carcinoma

Abstract

Context Aaptamine is a potent ocean-derived non-traditional drug candidate against human cancers. However, the underlying molecular mechanisms governing aaptamine-mediated repression of lung cancer cells remain largely undefined. Objective To examine the inhibitory effect of aaptamine on proliferation and progression of non-small cell lung carcinoma (NSCLC) and dissect the potential mechanisms involved in its anticancer functions. Materials and methods In vitro assays of cell proliferation, cell cycle analysis, clonal formation, apoptosis and migration were performed to examine the inhibitory effects of aaptamine (8, 16 and 32 μg/mL) on NSCLC cells. The expression levels of proteins were analysed using western blotting analysis when cells were treated with a single drug or a combination treatment for 48 h. Results Aaptamine significantly inhibited A549 and H1299 cells proliferation with IC 50 values of 13.91 and 10.47 μg/mL. At the concentrations of 16 and 32 μg/mL, aaptamine significantly reduced capacities in clonogenicity, enhanced cellular apoptosis and decreased the motile and invasive cellular phenotype. In addition, aaptamine arrested cell cycle at G1 phase via selectively abating cell cycle regulation drivers (CDK2/4 and Cyclin D1/E). Western blotting results showed that aaptamine attenuated the protein expression of MMP-7, MMP-9 and upregulated the expression of cleaved-PARP and cleaved-caspase 3. Moreover, aaptamine inhibited PI3K/AKT/GSK3β signalling cascades through specifically degrading the phosphorylated AKT and GSK3β. Discussion and conclusions Aaptamine retarded the proliferation and invasion of NSCLC cells by selectively targeting the pathway PI3K/AKT/GSK3β suggesting it as a potential chemotherapeutic agent for repressing tumorigenesis and progression of NSCLC in humans.

Biological Activity of Naturally Derived Naphthyridines

“…The anticancer activity of the compound 16 has been extensively researched. Aaptamine exhibited notable cytotoxic effects in vitro against H1299 and A549 non-small cell lung cancer [ 20 ], HeLa cervical cancer [ 21 ], and CEM-SS T-lymphoblastic leukemia cell lines [ 22 ], with IC 50 values ranging from 10.47 to 15.03 μg/mL. Moreover, aaptamine 16 displayed a potent anticancer effect in mice carrying human hepatocellular carcinoma HCC-LM3 xenografts with downregulation of SOX9 and Ki67 expression [ 23 ].…”

“…Aaptamine 16 expressed the ability to interfere specifically with p53 and c-myc network in NT2 human embryonal carcinoma cell line [ 26 ]. Gong et al [ 20 ] performed further investigation of the mechanism of aaptamine 16 action in non-small cell lung cancer cell lines. The agent 16 displayed antiproliferative properties with inhibition of cancer cells growth and clonogenicity in a dose-dependent manner.…”

“…Aaptamine induced G1 cell cycle arrest with a reduction of CDK2 (Cyclin-dependent kinase 2), CDK4 (Cyclin-dependent kinase 4), Cyclin D1, and Cyclin E levels, and also interfered with the PI3K/AKT/GSK3b (phosphatidylinositol-3 kinase/protein kinase B/glycogen synthase kinase 3 beta) axis. It could potentially diminish the process of metastasis and tumor invasion due to downregulation of MMP-7 (matrix metalloproteinase-7) and MMP-9 (matrix metalloproteinase-9) expression [ 20 ]. Beside anticancer activity, aaptamine 16 was shown to block α-adrenoceptors in vascular smooth muscles [ 27 ].…”

Bioinformatics Analysis Predicts hsa_circ_0026337/miR-197-3p as a Potential Oncogenic ceRNA Network for Non-Small Cell Lung Cancers

“…These ndings indicated that circRNAs are closely related to the occurrence and development of diseases and maybe a potential target for the future diagnosis and treatment of the disease. However, most of the studies on circular RNA and non-small cell lung describe only a few genes description, and the mechanism of systematic molecular regulation is yet to be elucidated [21][22].…”

Effects of Sponge-Derived Alkaloids on Activities of the Bacterial α-D-Galactosidase and Human Cancer Cell α-N-Acetylgalactosaminidase

“…All these compounds have either an N-methylated or a non-N-methylated 1,6-naphthyridine core fused with a functionalized benzenoid unit. Some of aaptamines have been reported to have α-adrenoceptor blocking [ 12 ], anti-HIV-1 [ 13 , 14 ], antimycobacterial [ 13 , 14 , 15 ], antiherpes [ 16 ], and anticancer activity [ 17 ]. Aaptamine and its congeners were shown to act as inhibitors of different enzymes.…”