Abstract
Malformin C, a fungal cyclic pentapeptide, has been claimed to have anti-cancer potential, but no in vivo study was available to substantiate this property. Therefore, we conducted in vitro and in vivo experiments to investigate its anti-cancer effects and toxicity. Our studies showed Malformin C inhibited Colon 38 and HCT 116 cell growth dose-dependently with an IC50 of 0.27±0.07μM and 0.18±0.023μM respectively. This inhibition was explicated by Malformin C’s effect on G2/M arrest. Moreover, we observed up-regulated expression of phospho-histone H2A.X, p53, cleaved CASPASE 3 and LC3 after Malformin C treatment, while the apoptosis assay indicated an increased population of necrotic and late apoptotic cells. In vivo, the pathological study exhibited the acute toxicity of Malformin C at lethal dosage in BDF1 mice might be caused by an acute yet subtle inflammatory response, consistent with elevated IL-6 in the plasma cytokine assay. Further anti-tumor and toxicity experiments proved that 0.3mg/kg injected weekly was the best therapeutic dosage of Malformin C in Colon 38 xenografted BDF1 mice, whereas 0.1mg/kg every other day showed no effect with higher resistance, and 0.9mg/kg per week either led to fatal toxicity in seven-week old mice or displayed no advantage over 0.3mg/kg group in nine-week old mice. Overall, we conclude that Malformin C arrests Colon 38 cells in G2/M phase and induces multiple forms of cell death through necrosis, apoptosis and autophagy. Malformin C has potent cell growth inhibition activity, but the therapeutic index is too low to be an anti-cancer drug.
Highlights
Malformins are a group of cyclic pentapeptides originally discovered and isolated from culture filtrate of the fungus Aspergillus niger, and it induces the malformations of bean plants and curvatures of corn roots [1, 2]
Malformin C had different inhibition effects among different cancer cell lines (P
The actions of Malformin C on the colony-forming ability of Colon 38 and HCT116 were determined as the percentage of visible colony numbers of drug-treated group compared to non-treatment control group by clonogenic assay
Summary
Malformins are a group of cyclic pentapeptides originally discovered and isolated from culture filtrate of the fungus Aspergillus niger, and it induces the malformations of bean plants and curvatures of corn roots [1, 2]. Study of Malformin C as an Anti-Cancer Drug doi:10.1371/journal.pone.0140069.g001. As the first discovered sub-group, Malformin A mainly consists of Malformin A1, A2, A3 and A4 [5, 6], in which Malformin A1 is most well-studied, and its biological activities have been reported including malformations of plants, antibiotic effects against certain bacteria species [7], enhancement of fibrinolytic activity [8, 9], and prevention against IL1-induced procoagulant reaction [10]. Malformin C is a relatively new and toxic member of Malformins [11] (Fig 1A). It has shown antibacterial activity [12], as well as potent antimalarial and antitrypanosomal properties [13]. We carried out a series of preliminary in vitro and in vivo studies to explore Malformin C’s anti-cancer effects and its in vivo toxicity
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