Skip to main content
Top
Published in: Cancer Cell International 1/2010

Open Access 01-12-2010 | Primary research

Up-regulation of p21 and TNF-α is mediated in lycorine-induced death of HL-60 cells

Authors: Jing Liu, Ji-liang Hu, Bi-Wei Shi, Yan He, Wei-Xin Hu

Published in: Cancer Cell International | Issue 1/2010

Login to get access

Abstract

Background

Leukemia is one of the most life-threatening cancers today, and acute promyelogenous leukemia (APL) is a common type of leukemia. Many natural compounds have already been found to exhibit significant anti-tumor effects. Lycorine, a natural alkaloid extracted from Amaryllidaceae, exhibited anti-leukemia effects in vitro and in vivo. The survival rate of HL-60 cells exposed to lycorine was decreased, cell growth was slowed down, and cell regeneration potential was inhibited. HL-60 cells exhibited typical apoptotic characteristic. Lycorine can suppress leukemia growth and reduce cell survival and inducing apoptosis of tumor cells. The purpose of this work is to elucidate the mechanism by which lycorine induces APL cells.

Results

When HL-60 cells were treated with different concentration of lycorine, the expression of p21 and TNF-α was up-regulated in a concentration-dependent manner as shown by real-time quantitative reverse transcriptase-polymerase chain reaction and Western blotting. Lycorine also down-regulated p21-related gene expression, including Cdc2, Cyclin B, Cdk2 and Cyclin E, promoted Bid truncation, decreased IκB phosphorylation and blocked NF-κB nuclear import. Cytochrome c was released from mitochondria as observed with confocal laser microscopy.

Conclusions

The TNF-α signal transduction pathway and p21-mediated cell-cycle inhibition were involved in the apoptosis of HL-60 cells induced by lycorine. These results contribute to the development of new lycorine-based anti-leukemia drugs.
Appendix
Available only for authorised users
Literature
1.
go back to reference Hu W, Kavanagh JJ: Anticancer therapy targeting the apoptotic pathway. Lancet Oncol. 2003, 4: 721-729. 10.1016/S1470-2045(03)01277-4.CrossRefPubMed Hu W, Kavanagh JJ: Anticancer therapy targeting the apoptotic pathway. Lancet Oncol. 2003, 4: 721-729. 10.1016/S1470-2045(03)01277-4.CrossRefPubMed
2.
go back to reference Los M, Burek CJ, Stroh C, Benedyk K, Hug H, Mackiewicz A: Anticancer drugs of tomorrow: apoptotic pathways as targets for drug design. Drug Discov Today. 2003, 8: 67-77. 10.1016/S1359-6446(02)02563-1.CrossRefPubMed Los M, Burek CJ, Stroh C, Benedyk K, Hug H, Mackiewicz A: Anticancer drugs of tomorrow: apoptotic pathways as targets for drug design. Drug Discov Today. 2003, 8: 67-77. 10.1016/S1359-6446(02)02563-1.CrossRefPubMed
3.
4.
go back to reference Thompson CB: Apoptosis in the pathogenesis and treatment of disease. Science. 1995, 267: 1456-1462. 10.1126/science.7878464.CrossRefPubMed Thompson CB: Apoptosis in the pathogenesis and treatment of disease. Science. 1995, 267: 1456-1462. 10.1126/science.7878464.CrossRefPubMed
5.
go back to reference Gartel AL, Tyner AL: The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther. 2002, 1: 639-649.PubMed Gartel AL, Tyner AL: The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther. 2002, 1: 639-649.PubMed
6.
go back to reference Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA: Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma irradiation. Proc Natl Acad Sci USA. 1999, 96: 1002-1007. 10.1073/pnas.96.3.1002.PubMedCentralCrossRefPubMed Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA: Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma irradiation. Proc Natl Acad Sci USA. 1999, 96: 1002-1007. 10.1073/pnas.96.3.1002.PubMedCentralCrossRefPubMed
7.
go back to reference Kondo S, Barna BP, Kondo Y, Tanaka Y, Casey G, Liu J, Morimura T, Kaakaji R, Peterson JW, Werbel B, Barnett GH: WAF1/CIP1 increases the susceptibility of p53 non-functional malignant glioma cells to cisplatin-induced apoptosis. Oncogene. 1996, 13: 1279-1285.PubMed Kondo S, Barna BP, Kondo Y, Tanaka Y, Casey G, Liu J, Morimura T, Kaakaji R, Peterson JW, Werbel B, Barnett GH: WAF1/CIP1 increases the susceptibility of p53 non-functional malignant glioma cells to cisplatin-induced apoptosis. Oncogene. 1996, 13: 1279-1285.PubMed
8.
go back to reference Lincet H, Poulain L, Remy JS, Deslandes E, Duigou F, Gauduchon P, Staedel C: The p21(cip1/waf1) cyclin-dependent kinase inhibitor enhances the cytotoxic effect of cisplatin in human ovarian carcinoma cells. Cancer Lett. 2000, 161: 17-26. 10.1016/S0304-3835(00)00586-3.CrossRefPubMed Lincet H, Poulain L, Remy JS, Deslandes E, Duigou F, Gauduchon P, Staedel C: The p21(cip1/waf1) cyclin-dependent kinase inhibitor enhances the cytotoxic effect of cisplatin in human ovarian carcinoma cells. Cancer Lett. 2000, 161: 17-26. 10.1016/S0304-3835(00)00586-3.CrossRefPubMed
9.
go back to reference Zolota V, Sirinian C, Melachrinou M, Symeonidis A, Bonikos DS: Expression of the regulatory cell cycle proteins p21, p27, p14, p16, p53, mdm2, and cyclin E in bone marrow biopsies with acute myeloid leukemia. Correlation with patients' survival. Pathol Res Pract. 2007, 203: 199-207. 10.1016/j.prp.2007.01.010.CrossRefPubMed Zolota V, Sirinian C, Melachrinou M, Symeonidis A, Bonikos DS: Expression of the regulatory cell cycle proteins p21, p27, p14, p16, p53, mdm2, and cyclin E in bone marrow biopsies with acute myeloid leukemia. Correlation with patients' survival. Pathol Res Pract. 2007, 203: 199-207. 10.1016/j.prp.2007.01.010.CrossRefPubMed
10.
go back to reference Teicher BA: Next generation topoisomerase I inhibitors: rationale and biomarker strategies. Biochem Pharmacol. 2008, 75: 1262-1271. 10.1016/j.bcp.2007.10.016.CrossRefPubMed Teicher BA: Next generation topoisomerase I inhibitors: rationale and biomarker strategies. Biochem Pharmacol. 2008, 75: 1262-1271. 10.1016/j.bcp.2007.10.016.CrossRefPubMed
11.
go back to reference Mao X, Yu CR, Li WH, Li WX: Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells. Cell Res. 2008, 18: 879-888. 10.1038/cr.2008.86.CrossRefPubMed Mao X, Yu CR, Li WH, Li WX: Induction of apoptosis by shikonin through a ROS/JNK-mediated process in Bcr/Abl-positive chronic myelogenous leukemia (CML) cells. Cell Res. 2008, 18: 879-888. 10.1038/cr.2008.86.CrossRefPubMed
12.
go back to reference Jin W, Di G, Li J, Chen Y, Li W, Wu J, Cheng T, Yao M, Shao Z: TIEG1 induces apoptosis through mitochondrial apoptotic pathway and promotes apoptosis induced by homoharringtonine and velcade. FEBS Lett. 2007, 581: 3826-3832. 10.1016/j.febslet.2007.07.008.CrossRefPubMed Jin W, Di G, Li J, Chen Y, Li W, Wu J, Cheng T, Yao M, Shao Z: TIEG1 induces apoptosis through mitochondrial apoptotic pathway and promotes apoptosis induced by homoharringtonine and velcade. FEBS Lett. 2007, 581: 3826-3832. 10.1016/j.febslet.2007.07.008.CrossRefPubMed
13.
go back to reference Chen Y, Hu Y, Michaels S, Segal D, Brown D, Li S: Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia. 2009, 23: 1446-1454. 10.1038/leu.2009.52.PubMedCentralCrossRefPubMed Chen Y, Hu Y, Michaels S, Segal D, Brown D, Li S: Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia. 2009, 23: 1446-1454. 10.1038/leu.2009.52.PubMedCentralCrossRefPubMed
14.
go back to reference Cuendet M, Christov K, Lantvit DD, Deng Y, Hedayat S, Helson L, McChesney JD, Pezzuto JM: Multiple myeloma regression mediated by bruceantin. Clin Cancer Res. 2004, 10: 1170-1179. 10.1158/1078-0432.CCR-0362-3.CrossRefPubMed Cuendet M, Christov K, Lantvit DD, Deng Y, Hedayat S, Helson L, McChesney JD, Pezzuto JM: Multiple myeloma regression mediated by bruceantin. Clin Cancer Res. 2004, 10: 1170-1179. 10.1158/1078-0432.CCR-0362-3.CrossRefPubMed
15.
go back to reference Servida F, Soligo D, Delia D, Henderson C, Brancolini C, Lombardi L, Deliliers GL: Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I. Leukemia. 2005, 19: 2324-2332. 10.1038/sj.leu.2403987.CrossRefPubMed Servida F, Soligo D, Delia D, Henderson C, Brancolini C, Lombardi L, Deliliers GL: Sensitivity of human multiple myelomas and myeloid leukemias to the proteasome inhibitor I. Leukemia. 2005, 19: 2324-2332. 10.1038/sj.leu.2403987.CrossRefPubMed
16.
go back to reference Chanda SK, Caldwell JS: Fulfilling the promise: drug discovery in the post-genomic era. Drug Discov Today. 2003, 8: 168-174. 10.1016/S1359-6446(02)02595-3.CrossRefPubMed Chanda SK, Caldwell JS: Fulfilling the promise: drug discovery in the post-genomic era. Drug Discov Today. 2003, 8: 168-174. 10.1016/S1359-6446(02)02595-3.CrossRefPubMed
17.
go back to reference Berkov S, Codina C, Viladomat F, Bastida J: Alkaloids from Galanthus nivalis. Phytochemistry. 2007, 68: 1791-1798. 10.1016/j.phytochem.2007.03.025.CrossRefPubMed Berkov S, Codina C, Viladomat F, Bastida J: Alkaloids from Galanthus nivalis. Phytochemistry. 2007, 68: 1791-1798. 10.1016/j.phytochem.2007.03.025.CrossRefPubMed
18.
go back to reference Li SY, Chen C, Zhang HQ, Guo HY, Wang H, Wang L, Zhang X, Hua SN, Yu J, Xiao PG, Li RS, Tan X: Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res. 2005, 67: 18-23. 10.1016/j.antiviral.2005.02.007.CrossRefPubMed Li SY, Chen C, Zhang HQ, Guo HY, Wang H, Wang L, Zhang X, Hua SN, Yu J, Xiao PG, Li RS, Tan X: Identification of natural compounds with antiviral activities against SARS-associated coronavirus. Antiviral Res. 2005, 67: 18-23. 10.1016/j.antiviral.2005.02.007.CrossRefPubMed
19.
go back to reference Liu J, Hu WX, He LF, Ye M, Li Y: Effects of lycorine on HL-60 cells via arresting cell cycle and inducing apoptosis. FEBS Lett. 2004, 578: 245-250. 10.1016/j.febslet.2004.10.095.CrossRefPubMed Liu J, Hu WX, He LF, Ye M, Li Y: Effects of lycorine on HL-60 cells via arresting cell cycle and inducing apoptosis. FEBS Lett. 2004, 578: 245-250. 10.1016/j.febslet.2004.10.095.CrossRefPubMed
20.
go back to reference Li Y, Liu J, Tang LJ, Shi YW, Ren W, Hu WX: Apoptosis induced by lycorine in KM3 cells is associated with the G0/G1 cell cycle arrest. Oncol Rep. 2007, 17: 377-384.PubMed Li Y, Liu J, Tang LJ, Shi YW, Ren W, Hu WX: Apoptosis induced by lycorine in KM3 cells is associated with the G0/G1 cell cycle arrest. Oncol Rep. 2007, 17: 377-384.PubMed
21.
go back to reference Liu XS, Jiang J, Jiao XY, Wu YE, Lin JH, Cai YM: Lycorine induces apoptosis and down-regulation of Mcl-1 in human leukemia cells. Cancer Lett. 2009, 274: 16-24. 10.1016/j.canlet.2008.08.029.CrossRefPubMed Liu XS, Jiang J, Jiao XY, Wu YE, Lin JH, Cai YM: Lycorine induces apoptosis and down-regulation of Mcl-1 in human leukemia cells. Cancer Lett. 2009, 274: 16-24. 10.1016/j.canlet.2008.08.029.CrossRefPubMed
22.
go back to reference Lamoral-Theys D, Andolfi A, Van Goietsenoven G, Cimmino A, Le Calvé B, Wauthoz N, Mégalizzi V, Gras T, Bruyère C, Dubois J, Mathieu V, Kornienko A, Kiss R, Evidente A: Lycorine, the main phenanthridine amaryllidaceae alkaloid, exhibits significant antitumour activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight. J Med Chem. 2009, 52: 6244-6256. 10.1021/jm901031h.PubMedCentralCrossRefPubMed Lamoral-Theys D, Andolfi A, Van Goietsenoven G, Cimmino A, Le Calvé B, Wauthoz N, Mégalizzi V, Gras T, Bruyère C, Dubois J, Mathieu V, Kornienko A, Kiss R, Evidente A: Lycorine, the main phenanthridine amaryllidaceae alkaloid, exhibits significant antitumour activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight. J Med Chem. 2009, 52: 6244-6256. 10.1021/jm901031h.PubMedCentralCrossRefPubMed
23.
go back to reference Liu J, Li Y, Tang LJ, Shi YW, Zhang GP, Hu WX: Treatment of lycorine on SCID mice model with human APL cells. Biomed Pharmacother. 2007, 61: 229-234. 10.1016/j.biopha.2007.01.003.CrossRefPubMed Liu J, Li Y, Tang LJ, Shi YW, Zhang GP, Hu WX: Treatment of lycorine on SCID mice model with human APL cells. Biomed Pharmacother. 2007, 61: 229-234. 10.1016/j.biopha.2007.01.003.CrossRefPubMed
24.
go back to reference McNulty J, Nair JJ, Bastida J, Pandey S, Griffin C: Structure-activity studies on the lycorine pharmacophore: A potent inducer of apoptosis in human leukemia cells. Phytochemistry. 2009, 70: 913-919. 10.1016/j.phytochem.2009.04.012.CrossRefPubMed McNulty J, Nair JJ, Bastida J, Pandey S, Griffin C: Structure-activity studies on the lycorine pharmacophore: A potent inducer of apoptosis in human leukemia cells. Phytochemistry. 2009, 70: 913-919. 10.1016/j.phytochem.2009.04.012.CrossRefPubMed
25.
go back to reference Abukhdeir AM, Park BH: P21 and p27: roles in carcinogenesis and drug resistance. Expert Rev Mol Med. 2008, 1: 10-19. Abukhdeir AM, Park BH: P21 and p27: roles in carcinogenesis and drug resistance. Expert Rev Mol Med. 2008, 1: 10-19.
26.
go back to reference Delk NA, Hunt KK, Keyomarsi K: Altered subcellular localization of tumour-specific cyclin E isoforms affects cyclin-dependent kinase 2 complex formation and proteasomal regulation. Cancer Res. 2009, 69: 2817-2825. 10.1158/0008-5472.CAN-08-4182.PubMedCentralCrossRefPubMed Delk NA, Hunt KK, Keyomarsi K: Altered subcellular localization of tumour-specific cyclin E isoforms affects cyclin-dependent kinase 2 complex formation and proteasomal regulation. Cancer Res. 2009, 69: 2817-2825. 10.1158/0008-5472.CAN-08-4182.PubMedCentralCrossRefPubMed
27.
go back to reference Bartek J, Lukas J: Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 2003, 3: 421-429. 10.1016/S1535-6108(03)00110-7.CrossRefPubMed Bartek J, Lukas J: Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell. 2003, 3: 421-429. 10.1016/S1535-6108(03)00110-7.CrossRefPubMed
28.
go back to reference Rokudai S, Aikawa Y, Tagata Y, Tsuchida N, Taya Y, Kitabayashi I: Monocytic leukemia zinc finger (MOZ) interacts with p53 to induce p21 expression and cell-cycle arrest. J Biol Chem. 2009, 284: 237-244. 10.1074/jbc.M805101200.CrossRefPubMed Rokudai S, Aikawa Y, Tagata Y, Tsuchida N, Taya Y, Kitabayashi I: Monocytic leukemia zinc finger (MOZ) interacts with p53 to induce p21 expression and cell-cycle arrest. J Biol Chem. 2009, 284: 237-244. 10.1074/jbc.M805101200.CrossRefPubMed
29.
go back to reference Pincheira R, Castro AF, Ozes ON, Idumalla PS, Donner DB: Type 1 TNF receptor forms a complex with and uses Jak2 and c-Src to selectively engage signalling pathways that regulate transcription factor activity. J Immunol. 2008, 181: 1288-1298.CrossRefPubMed Pincheira R, Castro AF, Ozes ON, Idumalla PS, Donner DB: Type 1 TNF receptor forms a complex with and uses Jak2 and c-Src to selectively engage signalling pathways that regulate transcription factor activity. J Immunol. 2008, 181: 1288-1298.CrossRefPubMed
30.
go back to reference Hoffmann A, Natoli G, Ghosh G: Transcriptional regulation via the NF-kappa B signalling module. Oncogene. 2006, 25: 6706-6716. 10.1038/sj.onc.1209933.CrossRefPubMed Hoffmann A, Natoli G, Ghosh G: Transcriptional regulation via the NF-kappa B signalling module. Oncogene. 2006, 25: 6706-6716. 10.1038/sj.onc.1209933.CrossRefPubMed
32.
go back to reference Zhang L, Blackwell K, Thomas GS, Sun S, Yeh WC, Habelhah H: TRAF2 suppresses basal IKK activity in resting cells and TNF-α can activate IKK in TRAF2 and TRAF5 double knockout cells. J Mol Biol. 2009, 389: 495-510. 10.1016/j.jmb.2009.04.054.PubMedCentralCrossRefPubMed Zhang L, Blackwell K, Thomas GS, Sun S, Yeh WC, Habelhah H: TRAF2 suppresses basal IKK activity in resting cells and TNF-α can activate IKK in TRAF2 and TRAF5 double knockout cells. J Mol Biol. 2009, 389: 495-510. 10.1016/j.jmb.2009.04.054.PubMedCentralCrossRefPubMed
33.
go back to reference Manna SK, Haridas V, Aggarwal BB: Bcl-x(L) suppresses TNF-mediated apoptosis and activation of nuclear factor-kappa B, activation protein-1, and c-Jun N-terminal kinase. J Interferon Cytokine Res. 2000, 20: 725-735. 10.1089/10799900050116435.CrossRefPubMed Manna SK, Haridas V, Aggarwal BB: Bcl-x(L) suppresses TNF-mediated apoptosis and activation of nuclear factor-kappa B, activation protein-1, and c-Jun N-terminal kinase. J Interferon Cytokine Res. 2000, 20: 725-735. 10.1089/10799900050116435.CrossRefPubMed
34.
go back to reference Escárcega RO, Fuentes-Alexandro S, García-Carrasco M, Gatica A, Zamora A: The transcription factor nuclear factor-kappa B and cancer. Clin Oncol. 2007, 19: 154-161. 10.1016/j.clon.2006.11.013.CrossRef Escárcega RO, Fuentes-Alexandro S, García-Carrasco M, Gatica A, Zamora A: The transcription factor nuclear factor-kappa B and cancer. Clin Oncol. 2007, 19: 154-161. 10.1016/j.clon.2006.11.013.CrossRef
Metadata
Title
Up-regulation of p21 and TNF-α is mediated in lycorine-induced death of HL-60 cells
Authors
Jing Liu
Ji-liang Hu
Bi-Wei Shi
Yan He
Wei-Xin Hu
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2010
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-10-25

Other articles of this Issue 1/2010

Cancer Cell International 1/2010 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine