Study of Malformin C, a Fungal Source Cyclic Pentapeptide, as an Anti-Cancer Drug

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.

Diversity in Secondary Metabolites Including Mycotoxins from Strains of Aspergillus Section Nigri Isolated from Raw Cashew Nuts from Benin, West Africa

“…Asperazine was reported to have significant in vitro cytotoxicity against human leukemia [ 52 ] but no in vivo including bioavailability studies confirmed this. Malformins are currently being investigated for anti-cancer drug potential [ 53 ]. Altogether there are very few studies on other effects than in-vitro or in older studies intraperitoneal injection of compounds.…”

Structural Diversity and Biological Activities of Fungal Cyclic Peptides, Excluding Cyclodipeptides

“…Malformin A1 ( 114 ) from Aspergillus niger and Aspergillus tubingensis showed malformation activity in the corn root, and cytotoxic activity, and anti-TMV activity [ 89 , 90 , 92 , 93 ]. Malformin C ( 119 ) from Aspergillus niger had potent cell growth inhibition activity [ 94 ], but its therapeutic index was too low to be an anti-cancer drug [ 95 ].…”

Calm Before the Storm: A Glimpse into the Secondary Metabolism of Aspergillus welwitschiae, the Etiologic Agent of the Sisal Bole Rot

“…Malformin C has been previously detected in isolates of Aspergillus niger [27,28] and A. tubingensis [29,30], but not in A. welwitschiae . Genomics-wise, a single protein has been described as essential for the synthesis of this compound [18], which we used as a reference in our analysis.…”