Anti-lung cancer activity and inhibitory mechanisms of a novel Calothrixin A derivative

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.

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.

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.

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.