• Mycobiology
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• v.50 no.5
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• pp.389-398
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• 2022

Endophytic fungi are promising sources for the production of podophyllotoxin-an important anticancer compound, replacing depleted medical plants. In this study, the endophytes associated with Dysosma difformis-an ethnomedicinal plant species were isolated to explore novel sources of podophyllotoxin. Fifty-three endophytic fungi were isolated and identified by morphological observation and ITS-based rDNA sequencing, assigning them to 27 genera in 3 divisions. Fusarium was found the most prevalent genus with a colonization frequency of 11.11%, followed by Trametes (9.26%) and Penicillium (7.41%). Phylogenetic trees were constructed for the endophytic fungi community in two collection sites, Ha Giang and Lai Chau, revealing the adaptation of the species to the specific tissues and habitats. Cytotoxic activity of endophytic fungal extracts was investigated on cancer cell lines such as SK-LU-1, HL-60, and HepG2, demonstrating strong anti-cancer activity of six isolates belonging to Penicillium, Trametes, Purpureocillium, Aspergillus, and Ganoderma with IC₅₀ value of lower than 10 ㎍/mL. The presence of podophyllotoxin was indicated in Penicillium, Trametes, Aspergillus and for the first time in Purpureocillium and Ganoderma via high-performance liquid chromatography, which implied them as a potential source of this anticancer compound.

• Archives of Pharmacal Research
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• v.22 no.2
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• pp.208-212
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• 1999

Activity-guided fractionation of the roots of Anthriscus sylvestris resulted in the isolated and characterization of five cytotoxic compounds, deoxypodophyllotoxin (1), falcarindiol (2), and angeloyl podophyllotoxin (5) from the hexane soluble fraction and morelensin (3), bursehernin (4) from the choloroform soluble fraction. It is the first report of the occurrence of compound 5 in nature.

• Biomolecules & Therapeutics
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• v.29 no.6
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• pp.658-666
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• 2021

Podophyllotoxin (PT), a lignan compound from the roots and rhizomes of Podophyllum peltatum, has diverse pharmacological activities including anticancer effect in several types of cancer. The molecular mechanism of the anticancer effects of PT on colorectal cancer cells has not been reported yet. In this study, we sought to evaluate the anticancer effect of PT on human colorectal cancer HCT116 cells and identify the detailed molecular mechanism. PT inhibited the growth of cells and colony formation in a concentration-dependent manner and induced apoptosis as determined by the annexin V/7-aminoactinomycin D double staining assay. PT-induced apoptosis was accompanied by cell cycle arrest in the G2/M phase and an increase in the generation of reactive oxygen species (ROS). The effects of PT on the induction of ROS and apoptosis were prevented by pretreatment with N-acetyl-L-cysteine (NAC), indicating that an increase in ROS generation mediates the apoptosis of HCT116 cells induced by PT. Furthermore, Western blot analysis showed that PT upregulated the level of phospho (p)-p38 mitogen-activated protein kinase (MAPK). The treatment of SB203580, a p38 inhibitor, strongly prevented the apoptosis induced by PT, suggesting that PT-induced apoptosis involved the p38 MAPK signaling pathway. In addition, PT induced the loss of mitochondrial membrane potential and multi-caspase activation. The results suggested that PT induced cell cycle arrest in the G2/M phase and apoptosis through the p38 MAPK signaling pathway by upregulating ROS in HCT116 cells.

• Plant Biotechnology Reports
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• v.5 no.4
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• pp.367-373
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• 2011

Linum album accumulates anti-tumor podophyllotoxin (PTOX) and its related lignans, which were originally isolated from an endangered species Podophyllum. In the present study, we examined the effects of five fungal extracts on the production of lignans in L. album cell cultures. Fusarium graminearum extract induced the highest increase of PTOX [$143{\mu}g\;g^{-1}$ dry weight (DW) of the L. album cell culture], while Rhizopus stolonifer extract enhanced the accumulation of lariciresinol up to $364{\mu}g\;g^{-1}$ DW, instead of PTOX. Typical elicitors, such as chitin, chitosan, or methyl jasmonate (MeJA), were shown to be less effective in lignan production in L. album cell cultures. These results verified the advantages of fungal extracts to increase lignan production in L. album cell culture, and suggested potential on-demand metabolic engineering of lignan biosynthesis using differential fungal extracts.

• Journal of Korean Neurosurgical Society
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• v.63 no.6
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• pp.698-706
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• 2020

Objective : To study the physiochemical characteristics of podophyllotoxin (PPT) conjugated stearic acid grafted chitosan oligosaccharide micelle (PPT-CSO-SA), and evaluate the ability of the potential antineoplastic effects against glioma cells. Methods : PPT-CSO-SA was prepared by a dialysis method. The quality of PPT-CSO-SA including micellar size, zeta potential, drug encapsulation efficiency and drug release profiles was evaluated. Glioma cells were cultured and treated with PPT and PPT-CSO-SA. The ability of glioma cells to uptake PPT-CSO-SA was observed. The proliferation of glioma cells was determined by 3-[4, 5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide (MTT) assay. The apoptosis and morphology of U251 cells were observed by 4',6-Diamidino-2-phenylindole dihydrochloride (DAPI) dye staining. Cell cycle analysis was performed by flow cytometry. The migration ability of U251 cells was determined by wound healing test. Results : PPT-CSO-SA had nano-level particle size and sustained release property. The encapsulation efficiency of drug reached a high level. The cellular uptake percentage of PPT in glioma cells was lower than that of PPT-CSO-SA (p<0.05). The inhibitory effect of PPT-CSO-SA on glioma cells proliferation was significantly stronger than that of PPT (p<0.05). The morphologic change of apoptosis cell such as shrinkage, karyorrhexis and karyopyknosis were observed. The percentage of U251 cells in G2/M phase increased significantly in the PPT-CSO-SA group compared with PPT group (p<0.05). Compared with the PPT group, the cell migration ability of the PPT-CSO-SA group was significantly inhibited after 12 and 24 hours (p<0.05). Conclusion : PPT-CSO-SA can effectively enhance the glioma cellular uptake of drugs, inhibit glioma cells proliferation and migration, induce G2/M phase arrest of them, and promote their apoptosis. It may be a promising anti-glioma nano-drug.

• Tuberculosis and Respiratory Diseases
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• v.67 no.2
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• pp.145-147
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• 2009

Etoposide is a semi-synthetic derivative of podophyllotoxin that is effective against many cancers including small cell lung cancer. We report a case of etoposide-induced anaphylaxis in a 51-year-old woman who tolerated etoposide during her first cycle chemotherapy regimen. During the second cycle, she complained of generalized urticaria and dyspnea 5 minutes after being infused with etoposide. She recovered completely with antihistamine, corticosteroid and fluid replacement. The intradermal skin test with etoposide showed a clear positive immediate reaction. This case suggests that etoposide can induce IgE-mediated anaphylaxis.

• Journal of Microbiology and Biotechnology
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• v.31 no.12
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• pp.1615-1623
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• 2021

Picropodophyllotoxin (PPT), an epimer of podophyllotoxin, is derived from the roots of Podophyllum hexandrum and exerts various biological effects, including anti-proliferation activity. However, the effect of PPT on colorectal cancer cells and the associated cellular mechanisms have not been studied. In the present study, we explored the anticancer activity of PPT and its underlying mechanisms in HCT116 cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to monitor cell viability. Flow cytometry was used to evaluate cell cycle distribution, the induction of apoptosis, the level of reactive oxygen species (ROS), assess the mitochondrial membrane potential (Δψm), and multi-caspase activity. Western blot assays were performed to detect the expression of cell cycle regulatory proteins, apoptosis-related proteins, and p38 MAPK (mitogen-activated protein kinase). We found that PPT induced apoptosis, cell cycle arrest at the G1 phase, and ROS in the HCT116 cell line. In addition, PPT enhanced the phosphorylation of p38 MAPK, which regulates apoptosis and PPT-induced apoptosis. The phosphorylation of p38 MAPK was inhibited by an antioxidant agent (N-acetyl-L-cysteine, NAC) and a p38 inhibitor (SB203580). PPT induced depolarization of the mitochondrial inner membrane and caspase-dependent apoptosis, which was attenuated by exposure to Z-VAD-FMK. Overall, these data indicate that PPT induced G1 arrest and apoptosis via ROS generation and activation of the p38 MAPK signaling pathway.