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. 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. KEY FINDINGS: CAA45 significantly inhibited human non-small cancer cell A549 and NCI-H1650 cells growth with IC50 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. 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.
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Authors | Xiaohong Yang, Jiangsheng Gao, Jian Guo, Zimeng Zhao, Shao-Lin Zhang, Yun He |
Journal | Life sciences
(Life Sci)
Vol. 219
Pg. 20-30
(Feb 15 2019)
ISSN: 1879-0631 [Electronic] Netherlands |
PMID | 30605652
(Publication Type: Journal Article)
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Copyright | Copyright © 2018 Elsevier Inc. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- Indole Alkaloids
- Topoisomerase I Inhibitors
- calothrixin A
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Topics |
- A549 Cells
- Animals
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Apoptosis
(drug effects)
- Blotting, Western
- Cell Cycle
(drug effects)
- Cell Line, Tumor
- Cell Movement
(drug effects)
- Humans
- Indole Alkaloids
(pharmacology, therapeutic use)
- Lung Neoplasms
(drug therapy)
- Male
- Mice, Inbred BALB C
- Neoplasm Transplantation
- Topoisomerase I Inhibitors
(pharmacology, therapeutic use)
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