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Anti-lung cancer activity and inhibitory mechanisms of a novel Calothrixin A derivative.
- Source :
-
Life sciences [Life Sci] 2019 Feb 15; Vol. 219, pp. 20-30. Date of Electronic Publication: 2018 Dec 31. - Publication Year :
- 2019
-
Abstract
- Aims: CAA45 is a calothrixin A (CAA) analogue with anti-cancer activity at nanomolar concentration. This study aimed to investigate the anti-lung cancer activity of CAA45 and explore its mechanisms of actions.<br />Main Methods: CAA and CAA45 were synthesized and their inhibition on DNA topoisomerase I (Topo I) performed by evaluating the relaxation of supercoiled pBR322 plasmid DNA and their anti-lung cancer capacity determined by cytotoxic assays, cell migration, cell cycle, cell apoptosis, cell autophagy and related signaling proteins expression by western blot.<br />Key Findings: CAA45 significantly inhibited human non-small cancer cell A549 and NCI-H1650 cells growth with IC <subscript>50</subscript> values of 110 and 230 nM, respectively. In the A549 xenograft models, CAA45 displayed strong antitumor activities at a dose of 10 mg/kg. CAA45 inhibited Topo I activity and caused the cell cycle arrest at S phase, which also reduced A549 cell migration by inhibiting MMP-2 and MMP-9 expressions. Furthermore, CAA45 induced A549 cell apoptosis and autophagy. The apoptosis pathway was involved in the release of cytochrome c and caspase activation. CAA45 also inhibited Akt, activated JNK and up-regulated p53 signals in A549 cells, which may serve as a modulator to induce apoptosis and autophagy in cancer cells.<br />Significance: CAA45 exerted its anti-lung cancer effect via inhibition of Topo I, resulting in cell cycle arrest and cell migration, induction of mitochondria mediated cell apoptosis and autophagy via PI3K/Akt/JNK/p53 pathway. All these observations suggested that CAA45 could be a promising lead for anti-cancer drug discovery.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- A549 Cells
Animals
Antineoplastic Agents pharmacology
Apoptosis drug effects
Blotting, Western
Cell Cycle drug effects
Cell Line, Tumor
Cell Movement drug effects
Humans
Indole Alkaloids pharmacology
Male
Mice, Inbred BALB C
Neoplasm Transplantation
Topoisomerase I Inhibitors pharmacology
Topoisomerase I Inhibitors therapeutic use
Antineoplastic Agents therapeutic use
Indole Alkaloids therapeutic use
Lung Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0631
- Volume :
- 219
- Database :
- MEDLINE
- Journal :
- Life sciences
- Publication Type :
- Academic Journal
- Accession number :
- 30605652
- Full Text :
- https://doi.org/10.1016/j.lfs.2018.12.052