Study of malformin C, a fungal source cyclic pentapeptide, as an anti-cancer drug

Jing Wang, Zaoli Jiang, Wing Lam, Elizabeth A. Gullen, Zhe Yu, Ying Wei, Lihui Wang, Caroline Zeiss, Amanda P. Beck, Ee Chun Cheng, Chunfu Wu, Yung Chi Cheng, Yixuan Zhang

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13 Scopus citations

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 0.270.07IM and 0.180.023IM 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.

Original languageEnglish (US)
Article numbere0140069
JournalPLoS One
Volume10
Issue number11
DOIs
StatePublished - Nov 5 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Wang, J., Jiang, Z., Lam, W., Gullen, E. A., Yu, Z., Wei, Y., Wang, L., Zeiss, C., Beck, A. P., Cheng, E. C., Wu, C., Cheng, Y. C., & Zhang, Y. (2015). Study of malformin C, a fungal source cyclic pentapeptide, as an anti-cancer drug. PLoS One, 10(11), [e0140069]. https://doi.org/10.1371/journal.pone.0140069