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

Wang J, Jiang Z, Lam W, Gullen EA, Yu Z, Wei Y, Wang L, Zeiss C, Beck A, Cheng EC, Wu C, Cheng YC, Zhang Y - PLoS ONE (2015)

Bottom Line: This inhibition was explicated by Malformin C's effect on G2/M arrest.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Cell cycle analysis of Colon 38 cells treated by Malformin C and its combinations.(A) Chemical structure of Malformin C. Malformin C is a member of Malformins, a group of fungal cyclic pentapeptides. Its chemical formula is C23H39O5N5S2 with a molecular weight of 529.7. (B) Cell cycle progression of Colon 38 cells exposed to an increasing concentration of Malformin C for 24 hours. (C) Cell cycle progression of Colon 38 cells exposed to an increasing concentration of Malformin C for 48 hours. (D) The dose-dependent accumulation of G2-M phase Colon 38 cells treated by Malformin C at concentrations of 90 nM, 270 nM and 810 nM. Compared to the control group, the symbol Δ represented P<0.05, while * represented P<0.01. (E) Cell cycle analysis of Colon 38 cells treated with combinations of Malformin C and SN38. All the cells were exposed to respective compounds indicated above the graph for 24 hours and the analysis was done in duplicate. When treated with SN38, no significant changes of cell cycle progression were observed without or with different dosage of Malformin C.
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pone.0140069.g001: Cell cycle analysis of Colon 38 cells treated by Malformin C and its combinations.(A) Chemical structure of Malformin C. Malformin C is a member of Malformins, a group of fungal cyclic pentapeptides. Its chemical formula is C23H39O5N5S2 with a molecular weight of 529.7. (B) Cell cycle progression of Colon 38 cells exposed to an increasing concentration of Malformin C for 24 hours. (C) Cell cycle progression of Colon 38 cells exposed to an increasing concentration of Malformin C for 48 hours. (D) The dose-dependent accumulation of G2-M phase Colon 38 cells treated by Malformin C at concentrations of 90 nM, 270 nM and 810 nM. Compared to the control group, the symbol Δ represented P<0.05, while * represented P<0.01. (E) Cell cycle analysis of Colon 38 cells treated with combinations of Malformin C and SN38. All the cells were exposed to respective compounds indicated above the graph for 24 hours and the analysis was done in duplicate. When treated with SN38, no significant changes of cell cycle progression were observed without or with different dosage of Malformin C.

Mentions: 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 could also be obtained from the extract of Aspergillus tubingensis [3]. At present, three sub-groups of Malformins are identified, namely Malformin A, Malformin B [4], and Malformin C. 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]. Also, Malformin C inhibits bleomycin-induced G2 checkpoint in Jurkat cells [14], and was claimed to have potential in cancer treatment. However, no in vivo study has been presented to substantiate its anti-tumor property. Therefore, 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.


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

Wang J, Jiang Z, Lam W, Gullen EA, Yu Z, Wei Y, Wang L, Zeiss C, Beck A, Cheng EC, Wu C, Cheng YC, Zhang Y - PLoS ONE (2015)

Cell cycle analysis of Colon 38 cells treated by Malformin C and its combinations.(A) Chemical structure of Malformin C. Malformin C is a member of Malformins, a group of fungal cyclic pentapeptides. Its chemical formula is C23H39O5N5S2 with a molecular weight of 529.7. (B) Cell cycle progression of Colon 38 cells exposed to an increasing concentration of Malformin C for 24 hours. (C) Cell cycle progression of Colon 38 cells exposed to an increasing concentration of Malformin C for 48 hours. (D) The dose-dependent accumulation of G2-M phase Colon 38 cells treated by Malformin C at concentrations of 90 nM, 270 nM and 810 nM. Compared to the control group, the symbol Δ represented P<0.05, while * represented P<0.01. (E) Cell cycle analysis of Colon 38 cells treated with combinations of Malformin C and SN38. All the cells were exposed to respective compounds indicated above the graph for 24 hours and the analysis was done in duplicate. When treated with SN38, no significant changes of cell cycle progression were observed without or with different dosage of Malformin C.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4635020&req=5

pone.0140069.g001: Cell cycle analysis of Colon 38 cells treated by Malformin C and its combinations.(A) Chemical structure of Malformin C. Malformin C is a member of Malformins, a group of fungal cyclic pentapeptides. Its chemical formula is C23H39O5N5S2 with a molecular weight of 529.7. (B) Cell cycle progression of Colon 38 cells exposed to an increasing concentration of Malformin C for 24 hours. (C) Cell cycle progression of Colon 38 cells exposed to an increasing concentration of Malformin C for 48 hours. (D) The dose-dependent accumulation of G2-M phase Colon 38 cells treated by Malformin C at concentrations of 90 nM, 270 nM and 810 nM. Compared to the control group, the symbol Δ represented P<0.05, while * represented P<0.01. (E) Cell cycle analysis of Colon 38 cells treated with combinations of Malformin C and SN38. All the cells were exposed to respective compounds indicated above the graph for 24 hours and the analysis was done in duplicate. When treated with SN38, no significant changes of cell cycle progression were observed without or with different dosage of Malformin C.
Mentions: 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 could also be obtained from the extract of Aspergillus tubingensis [3]. At present, three sub-groups of Malformins are identified, namely Malformin A, Malformin B [4], and Malformin C. 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]. Also, Malformin C inhibits bleomycin-induced G2 checkpoint in Jurkat cells [14], and was claimed to have potential in cancer treatment. However, no in vivo study has been presented to substantiate its anti-tumor property. Therefore, 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.

Bottom Line: This inhibition was explicated by Malformin C's effect on G2/M arrest.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus