Skip to main content
Top
Published in: Cancer Cell International 1/2013

Open Access 01-12-2013 | Primary research

Arsenic trioxide inhibits the proliferation of myeloma cell line through notch signaling pathway

Authors: Jiasheng Hu, Xiao Huang, Xiuli Hong, Quanyi Lu, Xiongpeng Zhu

Published in: Cancer Cell International | Issue 1/2013

Login to get access

Abstract

Arsenic Trioxide (ATO) has shown remarkable efficacy for the treatment of multiple myeloma (MM). However, the mechanism by which ATO exerts its inhibitory effect on the proliferation of myeloma cells remains to be clarified. We study the inhibitory effect of ATO at various concentrations on the proliferation of the myeloma cell line RPMI 8226 and discussed the molecular mechanism of ATO on myeloma cell line. Our results proved that ATO had a significant dose-dependent and time-dependent inhibitory effect on the expressions of the Notch receptor (Notch1) and Notch ligand (Jag2). Data from the real-time PCR assay showed that the mRNA expression levels of the Jag2 gene and its downstream gene Hes1 were both significantly down-regulated after the myeloma cells were treated with ATO while the expression of the tumor suppressor gene PTEN was up-regulated. These results elucidated the molecular mechanism underlying the ATO mediated inhibition of myeloma cell proliferation. This is the first report on the anti-myeloma activity in myeloma cells through inhibition of the Notch signaling pathway.
Appendix
Available only for authorised users
Literature
1.
go back to reference Lenhoff S, Hjorth M, Holmberg E: Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study. Nordic Myeloma Study Group. Blood. 2000, 95: 7-11.PubMed Lenhoff S, Hjorth M, Holmberg E: Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study. Nordic Myeloma Study Group. Blood. 2000, 95: 7-11.PubMed
2.
go back to reference Harousseau JL, Moreau P, Attal M, Facon T, Avet LH: Stem-cell transplantation in multiple myeloma. Best Pract Res Clin Haematol. 2005, 18: 603-618. 10.1016/j.beha.2005.01.005.CrossRefPubMed Harousseau JL, Moreau P, Attal M, Facon T, Avet LH: Stem-cell transplantation in multiple myeloma. Best Pract Res Clin Haematol. 2005, 18: 603-618. 10.1016/j.beha.2005.01.005.CrossRefPubMed
3.
go back to reference Kastrinakis NG, Gorgoulis VG, Foukas PG, Dimopoulos MA, Kittas C: Molecular aspects of multiple myeloma. Ann Oncol. 2000, 11: 1217-1228. 10.1023/A:1008331714186.CrossRefPubMed Kastrinakis NG, Gorgoulis VG, Foukas PG, Dimopoulos MA, Kittas C: Molecular aspects of multiple myeloma. Ann Oncol. 2000, 11: 1217-1228. 10.1023/A:1008331714186.CrossRefPubMed
4.
go back to reference Schwarzenbach H: Expression of MDR1/Pglycoprotein, the multidrug resistance protein MRP, and the lung-resistance protein LRP in multiple myeloma. Med Oncol. 2002, 19: 87-104. 10.1385/MO:19:2:87.CrossRefPubMed Schwarzenbach H: Expression of MDR1/Pglycoprotein, the multidrug resistance protein MRP, and the lung-resistance protein LRP in multiple myeloma. Med Oncol. 2002, 19: 87-104. 10.1385/MO:19:2:87.CrossRefPubMed
5.
go back to reference Kyle RA, Rajkumar SV: Multiple Myeloma. New Engl J Med. 2004, 351: 1860-1873. 10.1056/NEJMra041875.CrossRefPubMed Kyle RA, Rajkumar SV: Multiple Myeloma. New Engl J Med. 2004, 351: 1860-1873. 10.1056/NEJMra041875.CrossRefPubMed
6.
go back to reference Park WH, Seol JG, Kim ES: Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. Cancer Res. 2000, 60: 3065-3071.PubMed Park WH, Seol JG, Kim ES: Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin-dependent kinase inhibitor, p21, and apoptosis. Cancer Res. 2000, 60: 3065-3071.PubMed
7.
go back to reference Rousselot P, Larghero J, Labaume S: Arsenic trioxide is effective in the treatment of multiple myeloma in SCID mice. Eur J Haematol. 2004, 72: 166-171. 10.1046/j.0902-4441.2003.00194.x.CrossRefPubMed Rousselot P, Larghero J, Labaume S: Arsenic trioxide is effective in the treatment of multiple myeloma in SCID mice. Eur J Haematol. 2004, 72: 166-171. 10.1046/j.0902-4441.2003.00194.x.CrossRefPubMed
8.
go back to reference Campbell RA, Sanchez E, Steinberg JA: Antimyeloma effects of arsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid. Br J Haematol. 2007, 138: 467-478. 10.1111/j.1365-2141.2007.06675.x.CrossRefPubMed Campbell RA, Sanchez E, Steinberg JA: Antimyeloma effects of arsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid. Br J Haematol. 2007, 138: 467-478. 10.1111/j.1365-2141.2007.06675.x.CrossRefPubMed
9.
go back to reference Kalmadi SR, Hussein MA: The emerging role of arsenic trioxide as an immunomodulatory agent in the management of multiple myeloma. Acta Haematol. 2006, 116: 1-7. 10.1159/000092341.CrossRefPubMed Kalmadi SR, Hussein MA: The emerging role of arsenic trioxide as an immunomodulatory agent in the management of multiple myeloma. Acta Haematol. 2006, 116: 1-7. 10.1159/000092341.CrossRefPubMed
10.
go back to reference Berenson JR, Matous J, Swift RA, Mapes R, Morrison B, Yeh HS: A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res. 2007, 13: 1762-1768. 10.1158/1078-0432.CCR-06-1812.CrossRefPubMed Berenson JR, Matous J, Swift RA, Mapes R, Morrison B, Yeh HS: A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res. 2007, 13: 1762-1768. 10.1158/1078-0432.CCR-06-1812.CrossRefPubMed
11.
go back to reference Abou-Jawde RM, Reed J, Kelly M: Efficacy and safety results with the combination therapy of arsenic trioxide, dexamethasone, and ascorbic acid in multiple myeloma patients: a phase 2 trial. Med Oncol. 2006, 23: 263-272. 10.1385/MO:23:2:263.CrossRefPubMed Abou-Jawde RM, Reed J, Kelly M: Efficacy and safety results with the combination therapy of arsenic trioxide, dexamethasone, and ascorbic acid in multiple myeloma patients: a phase 2 trial. Med Oncol. 2006, 23: 263-272. 10.1385/MO:23:2:263.CrossRefPubMed
12.
go back to reference Hayashi T, Hideshima T, Akiyama M: Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow microenvironment. Mol Cancer Ther. 2002, 1: 851-860.PubMed Hayashi T, Hideshima T, Akiyama M: Arsenic trioxide inhibits growth of human multiple myeloma cells in the bone marrow microenvironment. Mol Cancer Ther. 2002, 1: 851-860.PubMed
13.
go back to reference Wu X, Shi J, Wu Y: Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2. Cancer Biol Ther. 2010, 10 (11): 1201-1214. 10.4161/cbt.10.11.13669.PubMedCentralCrossRefPubMed Wu X, Shi J, Wu Y: Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2. Cancer Biol Ther. 2010, 10 (11): 1201-1214. 10.4161/cbt.10.11.13669.PubMedCentralCrossRefPubMed
14.
go back to reference Osborne B, Miele L: Notch and the immune system. Immunity. 1999, 11: 653-663. 10.1016/S1074-7613(00)80140-5.CrossRefPubMed Osborne B, Miele L: Notch and the immune system. Immunity. 1999, 11: 653-663. 10.1016/S1074-7613(00)80140-5.CrossRefPubMed
15.
go back to reference Leong KG, Karsan A: Recent insights into the role of Notch signaling in tumorigenesis. Blood. 2006, 107: 2223-33. 10.1182/blood-2005-08-3329.CrossRefPubMed Leong KG, Karsan A: Recent insights into the role of Notch signaling in tumorigenesis. Blood. 2006, 107: 2223-33. 10.1182/blood-2005-08-3329.CrossRefPubMed
16.
go back to reference Jundt F, Anagnostopoulos I, Forster R: Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood. 2002, 99 (9): 3398-3403. 10.1182/blood.V99.9.3398.CrossRefPubMed Jundt F, Anagnostopoulos I, Forster R: Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood. 2002, 99 (9): 3398-3403. 10.1182/blood.V99.9.3398.CrossRefPubMed
17.
go back to reference Hubmann R, Schwarzmeier JD, Shehata M: Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood. 2002, 99: 3742-3747. 10.1182/blood.V99.10.3742.CrossRefPubMed Hubmann R, Schwarzmeier JD, Shehata M: Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood. 2002, 99: 3742-3747. 10.1182/blood.V99.10.3742.CrossRefPubMed
18.
go back to reference Tohda S, Nara N: Expression of Notch1 and Jagged1 proteins in acute myeloid leukemia cells. LeuK Lymphoma. 2001, 42: 467-472. 10.3109/10428190109064603.CrossRefPubMed Tohda S, Nara N: Expression of Notch1 and Jagged1 proteins in acute myeloid leukemia cells. LeuK Lymphoma. 2001, 42: 467-472. 10.3109/10428190109064603.CrossRefPubMed
19.
go back to reference Weijzen S, Zlobin A, Braid M: HPV16 E6 and E7 oncoproteins regulate notch-1 expression and cooperate to induce transformation. Cell Physiol. 2003, 194: 356-362. 10.1002/jcp.10217.CrossRef Weijzen S, Zlobin A, Braid M: HPV16 E6 and E7 oncoproteins regulate notch-1 expression and cooperate to induce transformation. Cell Physiol. 2003, 194: 356-362. 10.1002/jcp.10217.CrossRef
20.
go back to reference Weng AP, Nam Y, Wolfe MS: Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol. 2003, 23 (2): 655-664. 10.1128/MCB.23.2.655-664.2003.PubMedCentralCrossRefPubMed Weng AP, Nam Y, Wolfe MS: Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol. 2003, 23 (2): 655-664. 10.1128/MCB.23.2.655-664.2003.PubMedCentralCrossRefPubMed
21.
go back to reference Houde C, Li Y, Song L: Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines [J]. Blood. 2004, 104: 3697-3704. 10.1182/blood-2003-12-4114.CrossRefPubMed Houde C, Li Y, Song L: Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines [J]. Blood. 2004, 104: 3697-3704. 10.1182/blood-2003-12-4114.CrossRefPubMed
22.
go back to reference Lu Q, Lin X, Feng J: Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways. J Hematol Oncol. 2008, 1: 6-10. 10.1186/1756-8722-1-6.PubMedCentralCrossRefPubMed Lu Q, Lin X, Feng J: Phenylhexyl isothiocyanate has dual function as histone deacetylase inhibitor and hypomethylating agent and can inhibit myeloma cell growth by targeting critical pathways. J Hematol Oncol. 2008, 1: 6-10. 10.1186/1756-8722-1-6.PubMedCentralCrossRefPubMed
23.
go back to reference Wen J, Cheng HY, Feng Y: P38 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells. Br J Haematol. 2008, 140: 169-180.CrossRefPubMed Wen J, Cheng HY, Feng Y: P38 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells. Br J Haematol. 2008, 140: 169-180.CrossRefPubMed
24.
go back to reference Drobna Z, Jaspers I, Thomas DJ, Styblo M: Differential activation of AP-1 in human bladder epithelial cells by inorganic and methylated arsenicals. FASEB J. 2008, 17: 67-69. Drobna Z, Jaspers I, Thomas DJ, Styblo M: Differential activation of AP-1 in human bladder epithelial cells by inorganic and methylated arsenicals. FASEB J. 2008, 17: 67-69.
25.
go back to reference Davison K, Mann KK, Waxman S, Miller WH: JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells. Blood. 2004, 103: 3496-3502. 10.1182/blood-2003-05-1412.CrossRefPubMed Davison K, Mann KK, Waxman S, Miller WH: JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells. Blood. 2004, 103: 3496-3502. 10.1182/blood-2003-05-1412.CrossRefPubMed
26.
go back to reference Palomero T, Dominguez M, Ferrando AA: The role of the PTEN/AKT Pathway in NOTCH1- induced leukemia [J]. Cell Cycle. 2008, 7: 965-970. 10.4161/cc.7.8.5753.PubMedCentralCrossRefPubMed Palomero T, Dominguez M, Ferrando AA: The role of the PTEN/AKT Pathway in NOTCH1- induced leukemia [J]. Cell Cycle. 2008, 7: 965-970. 10.4161/cc.7.8.5753.PubMedCentralCrossRefPubMed
27.
go back to reference Palomero T, Sulis ML, Cortina M: Mutational Loss of PTEN induces resistance to Notch1 inhibition in T-cell leukemia [J]. Nat Med. 2007, 13: 1203-1210. 10.1038/nm1636.PubMedCentralCrossRefPubMed Palomero T, Sulis ML, Cortina M: Mutational Loss of PTEN induces resistance to Notch1 inhibition in T-cell leukemia [J]. Nat Med. 2007, 13: 1203-1210. 10.1038/nm1636.PubMedCentralCrossRefPubMed
28.
go back to reference Chen G, Wang Y, Huang H: Combination of DNA methylation inhibitor 5-azacytidine and arsenic trioxide has synergistic activity in myeloma. Eur J Haematol. 2009, 82: 176-83. 10.1111/j.1600-0609.2008.01189.x.CrossRefPubMed Chen G, Wang Y, Huang H: Combination of DNA methylation inhibitor 5-azacytidine and arsenic trioxide has synergistic activity in myeloma. Eur J Haematol. 2009, 82: 176-83. 10.1111/j.1600-0609.2008.01189.x.CrossRefPubMed
29.
go back to reference Lunghi P, Giuliani N, Mazzera L: Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways. Blood. 2008, 112: 2450-62. 10.1182/blood-2007-10-114348.CrossRefPubMed Lunghi P, Giuliani N, Mazzera L: Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways. Blood. 2008, 112: 2450-62. 10.1182/blood-2007-10-114348.CrossRefPubMed
30.
go back to reference Wen J, Feng Y, Huang W: Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition. Leuk Res. 2010, 34: 85-92. 10.1016/j.leukres.2009.05.024.CrossRefPubMed Wen J, Feng Y, Huang W: Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition. Leuk Res. 2010, 34: 85-92. 10.1016/j.leukres.2009.05.024.CrossRefPubMed
Metadata
Title
Arsenic trioxide inhibits the proliferation of myeloma cell line through notch signaling pathway
Authors
Jiasheng Hu
Xiao Huang
Xiuli Hong
Quanyi Lu
Xiongpeng Zhu
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2013
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/1475-2867-13-25

Other articles of this Issue 1/2013

Cancer Cell International 1/2013 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