- Volume 16 Issue 15
DOI QR Code
Viscum Album Var Hot Water Extract Mediates Anti-cancer Effects through G1 Phase Cell Cycle Arrest in SK-Hep1 Human Hepatocarcinoma cells
- Cruz, Joseph Flores dela (Department of Animal Life And Environmental Science, Molecular Biology And Biotechnology, Hankyong National University) ;
- Kim, Yeon Soo (Department of Animal Life And Environmental Science, Molecular Biology And Biotechnology, Hankyong National University) ;
- Lumbera, Wenchie Marie Lara (Department of Animal Life And Environmental Science, Molecular Biology And Biotechnology, Hankyong National University) ;
- Hwang, Seong Gu (Department of Animal Life And Environmental Science, Molecular Biology And Biotechnology, Hankyong National University)
- Published : 2015.10.06
Viscum album var (VAV) also known as mistletoe, has long been categorized as a traditional herbal medicine in Asia. In addition to its immunomodulating activities, mistletoe has also been used in the treatment of chronic hepatic disorders in China and Korea. There are numerous reports showing that VAV possesses anti-cancer effects, however influence on human hepatocarcinoma has never been elucidated. In the present study, hot water extracts of VAV was evaluated for its potential anti-cancer effect in vitro. SK-Hep1 cells were treated with VAV (50-400ug/ml) for both 24 and 48 hours then cell viability was measured by cell counting kit-8 (CCK-8). Flow cytometry analysis was used to measure the proportion of SK-Hep1 in the different stages of cell cycle. RT-PCR and Western blot analysis were conducted to measure expression of cell cycle arrest related genes and proteins respectively. VAV dose dependently inhibited the proliferation of SK-Hep1 cells without any cytotoxicity with normal Chang liver cell (CCL-13). Flow cytometry analysis showed that VAV extract inhibited the cell cycle of SK-Hep1 cells via G1 phase arrest. RT-PCR and Western blot analysis both revealed that cyclin dependent kinase 2 (Cdk2) and cyclin D1 gene expression were significantly down regulated while p21 was upregulated dose dependently by VAV treatment. Combined down regulation of Cdk2, Cyclin D1 and up regulation of p21 can result in cell death. These results indicate that VAV showed evidence of anti-cancer activity through G1 phase cell cycle arrest in SK-Hep1 cells.
- Agami R, Bernards R (2000). Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell, 102, 55-66. https://doi.org/10.1016/S0092-8674(00)00010-6
- Blasina A, Paegle E, McGowan C (1997). The role of inhibitory phosphorylation of CDC2 following DNA replication block and radiation-induced damage in human cells. Mol Biol Cell, 8, 1013-23. https://doi.org/10.1091/mbc.8.6.1013
- Bartek J, Lukas J (2001a). Mammalian G1- and S-phase checkpoints in response to DNA damage. Curr Opin Cell Biol, 13, 738-47. https://doi.org/10.1016/S0955-0674(00)00280-5
- Byambaragchaa M, dela Cruz J, Kh A, Hwang S (2014). Anticancer potential of an ethanol extract of saussurea involucrata against hepatic cancer cells in vitro. Asian Pac J Cancer Prev, 15, 7527-32. https://doi.org/10.7314/APJCP.2014.15.18.7527
- Byambaragchaa M, dela Cruz J, Kh A, Hwang S (2013). Anti-metastatic potential of ethanol extract of saussurea involucrata against hepatic Cancer in vitro. Asian Pac J Cancer Prev, 14, 5397-402 https://doi.org/10.7314/APJCP.2013.14.9.5397
- Chu X, dela Cruz J, Hwang S, Hong H (2014). Tumorigenic effects of endocrine-disrupting chemicals are alleviated by Licorice (Glycyrrhiza glabra) root extract through suppression of AhR expression in mammalian cells. Asian Pac J Cancer Prev, 15, 4809-13. https://doi.org/10.7314/APJCP.2014.15.12.4809
- Datta R, Hass R, Gunji H, et al (1992). Down-regulation of cell cycle control genes by ionizing radiation. Cell Growth Differ, 3, 637-44.
- Dela Cruz J, Kim D, Hwang S (2014) Anti cancer effects of cnidium officinale makino extract mediated through apoptosis and cell cycle arrest in the HT-29 colorectal cancer cell line. Asian Pac J Cancer Prev, 15, 5120.
- Dulic V, Kaufmann WK, Wilson SJ, et al (1994). p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell, 76, 1013-23. https://doi.org/10.1016/0092-8674(94)90379-4
- el-Deiry W, Harper J, O'Connor P, et al (1994). WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res, 54, 1169-74.
- Elledge, S (1996). Cell cycle checkpoints: preventing an identity crisis, Science, 74, 1664-72.
- Ernst E, Schmit K, Steuer-Vogt M (2003). Mistletoe for cancer? A systematic review of randomised controlled trials. Int J Cancer, 107, 262-7 https://doi.org/10.1002/ijc.11386
- Ernst, E (2006). Mistletoe as a treatment for cancer. BMJ Clinical research, 7582, 1282-83.
- Gao J, Xie L, Yang W et al (2012). Risk Factors of hepatocellular Carcinoma-Current Status and Perspectives. Asian Pac J Cancer Prev, 13, 743-52 https://doi.org/10.7314/APJCP.2012.13.3.743
- Grossarth-Maticek R, Kiene H, Baumgartner S, Ziegler R (2001). Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Alternative therapies in health and medicine, 7, 57.
- Jung H, Jo M, Kim H (2014). Extract of Saccharina japonica induces apoptosis companied by cell cycle arrest and endoplasmic reticulum stress in SK-Hep1 Human Hepatocellular Carcinoma cells. Asian Pac J Cancer Prev, 15, 2993-99. https://doi.org/10.7314/APJCP.2014.15.7.2993
- Kim J, Jayaprakasha GK, Vikram A, et al (2012). Methyl nomilinate from citrus can modulate cell cycle regulators to induce cytotoxicity in human colon cancer (SW480) cells in vitro. Toxicol in vitro, 26, 1216-23. https://doi.org/10.1016/j.tiv.2012.06.005
- Marvibaigi M, Supriyanto E, Amini N et al (2014). Preclinical and Clinical effects of Mistletoe against Breast cancer, Bio Med Res Int, 785479
- Miyakawa Y, Matsushime H (2001) Rapid downregulation of cyclin D1 mRNA and protein levels by ultraviolet irradiation in murine macrophage cells. Bioche. Biophys Res Commun, 284, 71-6. https://doi.org/10.1006/bbrc.2001.4950
- Muschel R, Zhang H, Iliakis G, et al (1991). Cyclin B expression in HeLa cells during the G2 block induced by ionizing radiation. Cancer Res, 51, 5113-17.
- Poon R, Jiang W, Toyoshima H, et al (1996). Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage. J Biol Chem, 6, 13283-91.
- Rhind N, Furnari B, Russell P (1997) Cdc2 tyrosine phosphorylation is required for the DNA damage checkpoint in fission yeast. Genes Dev, 11, 504-11. https://doi.org/10.1101/gad.11.4.504
- Smits V, Klompmaker R, Vallenius T, et al (2000). p21 inhibits Thr161 phosphorylation of Cdc2 to enforce the G2 DNA damage checkpoint. J Biol Chem, 275, 30638-43. https://doi.org/10.1074/jbc.M005437200
- Terada Y, Tatsuka M, Jinno S, Okayama H (1995) Requirement for tyrosine phosphorylation of Cdk4 in G1 arrest induced by ultraviolet irradiation. Nature, 376, 358-62. https://doi.org/10.1038/376358a0
- Torre L, Bray F, Siegel R, et al (2015). Global cancer Statistics, 2012. CA Cancer J Clin, 65, 87-108. https://doi.org/10.3322/caac.21262
- World Cancer Report (2014). World Health Organization. 9283204298.
- Zhan Q, Antinore J, Wang X, Carrier F, et al (1999). Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene, 18, 2892-900. https://doi.org/10.1038/sj.onc.1202667
- Ethanol extracts from the branch of Taxillus yadoriki parasitic to Neolitsea sericea induces cyclin D1 proteasomal degradation through cyclin D1 nuclear export vol.18, pp.1, 2018, https://doi.org/10.1186/s12906-018-2258-x