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Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1.
Arch Toxicol. 2002 Jun; 76(5-6):351-9.AT

Abstract

Wogonin and fisetin are flavonoids, which are widely distributed in plants. Our recent study demonstrated that, among seven structurally related flavonoids, wogonin and fisetin showed the most potent apoptosis-inducing activities in human promyeloleukemic cells HL-60. In the present investigation, we performed molecular studies to assess the apoptotic effects of wogonin and fisetin on hepatocellular carcinoma cells SK-HEP-1. Both wogonin and fisetin showed dose-dependent cytotoxic effects on SK-HEP-1 cells, accompanied by DNA fragmentation. Microscopic observation under Giemsa staining showed that wogonin and fisetin, at the dose of 80 microM, induced cellular swelling and the appearance of apoptotic bodies, characteristics of apoptosis, in SK-HEP-1 cells. Furthermore, flow cytometry analysis showed an increase of hypodiploid cells in wogonin- and fisetin-treated SK-HEP-1 cells. These data demonstrated that wogonin and fisetin were effective inducers of apoptosis in SK-HEP-1 cells. Treatment with an apoptosis-inducing concentration of wogonin or fisetin caused induction of caspase 3/CPP32 activity, but not of caspase 1 activity. In addition, a caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor Ac-YVAD-CHO, reversed the cytotoxic effects of wogonin and fisetin on SK-HEP-1 cells. Further, cleavage of caspase 3 substrates including poly(ADP-ribose) polymerase (PARP) and D4-GDI protein, and decrease of pro-caspase 3 protein were detected in wogonin- and fisetin-treated SK-HEP-1 cells. Increase of p53 protein was associated with wogonin- and fisetin-induced apoptosis; however, a p53-controlled gene, p21(Waf/Cip-1), was only induced in wogonin- (not fisetin-) treated SK-HEP-1 cells. Serum starvation elevated p21(Waf/Cip-1) protein expression, and enhanced the apoptotic induction activity of wogonin (not fiseitn) in SK-HEP-1 cells. Our study has provided molecular evidence to demonstrate that wogonin and fisetin had effective cytotoxic effects through apoptosis induction in hepatocellular carcinoma cells SK-HEP-1; activation of caspase 3 cascade, induction of p53 protein and alternative expression of p21(Waf/Cip-1) protein were involved.

Authors+Show Affiliations

Graduate Institute of Pharmacognosy Science, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan. yc3270@tmu.edu.twNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12107653

Citation

Chen, Yen-Chou, et al. "Wogonin and Fisetin Induction of Apoptosis Through Activation of Caspase 3 Cascade and Alternative Expression of P21 Protein in Hepatocellular Carcinoma Cells SK-HEP-1." Archives of Toxicology, vol. 76, no. 5-6, 2002, pp. 351-9.
Chen YC, Shen SC, Lee WR, et al. Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. Arch Toxicol. 2002;76(5-6):351-9.
Chen, Y. C., Shen, S. C., Lee, W. R., Lin, H. Y., Ko, C. H., Shih, C. M., & Yang, L. L. (2002). Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. Archives of Toxicology, 76(5-6), 351-9.
Chen YC, et al. Wogonin and Fisetin Induction of Apoptosis Through Activation of Caspase 3 Cascade and Alternative Expression of P21 Protein in Hepatocellular Carcinoma Cells SK-HEP-1. Arch Toxicol. 2002;76(5-6):351-9. PubMed PMID: 12107653.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. AU - Chen,Yen-Chou, AU - Shen,Shing-Chuan, AU - Lee,Woan-Rouh, AU - Lin,Hui-Yi, AU - Ko,Ching-Huai, AU - Shih,Chun-Ming, AU - Yang,Ling-Ling, Y1 - 2002/04/23/ PY - 2002/01/15/received PY - 2002/03/13/accepted PY - 2002/7/11/pubmed PY - 2003/3/5/medline PY - 2002/7/11/entrez SP - 351 EP - 9 JF - Archives of toxicology JO - Arch Toxicol VL - 76 IS - 5-6 N2 - Wogonin and fisetin are flavonoids, which are widely distributed in plants. Our recent study demonstrated that, among seven structurally related flavonoids, wogonin and fisetin showed the most potent apoptosis-inducing activities in human promyeloleukemic cells HL-60. In the present investigation, we performed molecular studies to assess the apoptotic effects of wogonin and fisetin on hepatocellular carcinoma cells SK-HEP-1. Both wogonin and fisetin showed dose-dependent cytotoxic effects on SK-HEP-1 cells, accompanied by DNA fragmentation. Microscopic observation under Giemsa staining showed that wogonin and fisetin, at the dose of 80 microM, induced cellular swelling and the appearance of apoptotic bodies, characteristics of apoptosis, in SK-HEP-1 cells. Furthermore, flow cytometry analysis showed an increase of hypodiploid cells in wogonin- and fisetin-treated SK-HEP-1 cells. These data demonstrated that wogonin and fisetin were effective inducers of apoptosis in SK-HEP-1 cells. Treatment with an apoptosis-inducing concentration of wogonin or fisetin caused induction of caspase 3/CPP32 activity, but not of caspase 1 activity. In addition, a caspase 3 inhibitor, Ac-DEVD-CHO, but not the caspase 1 inhibitor Ac-YVAD-CHO, reversed the cytotoxic effects of wogonin and fisetin on SK-HEP-1 cells. Further, cleavage of caspase 3 substrates including poly(ADP-ribose) polymerase (PARP) and D4-GDI protein, and decrease of pro-caspase 3 protein were detected in wogonin- and fisetin-treated SK-HEP-1 cells. Increase of p53 protein was associated with wogonin- and fisetin-induced apoptosis; however, a p53-controlled gene, p21(Waf/Cip-1), was only induced in wogonin- (not fisetin-) treated SK-HEP-1 cells. Serum starvation elevated p21(Waf/Cip-1) protein expression, and enhanced the apoptotic induction activity of wogonin (not fiseitn) in SK-HEP-1 cells. Our study has provided molecular evidence to demonstrate that wogonin and fisetin had effective cytotoxic effects through apoptosis induction in hepatocellular carcinoma cells SK-HEP-1; activation of caspase 3 cascade, induction of p53 protein and alternative expression of p21(Waf/Cip-1) protein were involved. SN - 0340-5761 UR - https://www.unboundmedicine.com/medline/citation/12107653/Wogonin_and_fisetin_induction_of_apoptosis_through_activation_of_caspase_3_cascade_and_alternative_expression_of_p21_protein_in_hepatocellular_carcinoma_cells_SK_HEP_1_ L2 - https://doi.org/10.1007/s00204-002-0346-6 DB - PRIME DP - Unbound Medicine ER -