title: 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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.|Department of Oncology and Hematology, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Zaoli
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Wing
authors.initials: W
authors.lastname: Lam
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Gullen
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yu
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Caroline
authors.initials: C
authors.lastname: Zeiss
authors.affiliation: Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Beck
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Ee-Chun
authors.initials: EC
authors.lastname: Cheng
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.affiliation: School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005656:Fungal Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D016195:G2 Phase / Q000187:drug effects; D045325:HCT116 Cells / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010456:Peptides, Cyclic / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D005656:Fungal Proteins; D010456:Peptides, Cyclic; C000608429:malformin C