Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition

Jianguo Wen, Yongdong Feng, Wanting Huang, Haiyun Chen, Bing Liao, Lawrence Rice, Hector A. Preti, Rammurti T. Kamble, Youli Zu, Douglas J. Ballon, Chung Che Chang

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The combination of ATO and bortezomib (ATO + bortezomib) has been recently shown to enhance antimyeloma activity; nevertheless, the mechanisms remained unclear in these studies. However, both bortezomib and ATO have been shown to activate the p38 MAPK pathway, which may counteract the enhancement induced by this combination. We studied the cytotoxicity of bortezomib, ATO, and ATO + bortezomib with or without inhibiting p38 MAPK, along with associated molecular changes in myeloma cells. The treatment of myeloma cells with ATO + bortezomib induced higher cytotoxicity than either agent alone. This increased cytotoxicity was further synergistically enhanced by inhibiting p38 MAPK. This effect was preserved in the presence of marrow stromal cells designed to simulate the tumor micro-environment and in the CD138+ neoplastic plasma cells directly isolated from myeloma patients. The enhanced cytotoxicity of ATO + bortezomib was associated with augmented STAT3 inhibition and JNK activation, up-regulation of Bim, p21, p27, p53 as well as down-regulation of Bcl-2. Furthermore, the synergistically potentiated apoptosis by p38 MAPK inhibition was associated with the attenuation of ATO + bortezomib-mediated activation of Hsp27 as well as the enhancement of ATO + bortezomib-mediated JNK activation, p53 up-regulation, and Bcl-2 down-regulation. The results suggest the opportunity for using p38 MAPK inhibition to enhance the efficacy of ATO + bortezomib in myeloma.

Original languageEnglish (US)
Pages (from-to)85-92
Number of pages8
JournalLeukemia Research
Volume34
Issue number1
DOIs
StatePublished - Jan 1 2010
Externally publishedYes

Fingerprint

p38 Mitogen-Activated Protein Kinases
Up-Regulation
Down-Regulation
Bortezomib
arsenic trioxide
Stromal Cells
Plasma Cells
Bone Marrow
Apoptosis

Keywords

  • ATO
  • Bortezomib
  • Myeloma
  • p38 MAPK

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition. / Wen, Jianguo; Feng, Yongdong; Huang, Wanting; Chen, Haiyun; Liao, Bing; Rice, Lawrence; Preti, Hector A.; Kamble, Rammurti T.; Zu, Youli; Ballon, Douglas J.; Chang, Chung Che.

In: Leukemia Research, Vol. 34, No. 1, 01.01.2010, p. 85-92.

Research output: Contribution to journalArticle

Wen, J, Feng, Y, Huang, W, Chen, H, Liao, B, Rice, L, Preti, HA, Kamble, RT, Zu, Y, Ballon, DJ & Chang, CC 2010, 'Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition', Leukemia Research, vol. 34, no. 1, pp. 85-92. https://doi.org/10.1016/j.leukres.2009.05.024
Wen, Jianguo ; Feng, Yongdong ; Huang, Wanting ; Chen, Haiyun ; Liao, Bing ; Rice, Lawrence ; Preti, Hector A. ; Kamble, Rammurti T. ; Zu, Youli ; Ballon, Douglas J. ; Chang, Chung Che. / Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition. In: Leukemia Research. 2010 ; Vol. 34, No. 1. pp. 85-92.
@article{ee42bcc7169549808af2e540e770b39c,
title = "Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition",
abstract = "The combination of ATO and bortezomib (ATO + bortezomib) has been recently shown to enhance antimyeloma activity; nevertheless, the mechanisms remained unclear in these studies. However, both bortezomib and ATO have been shown to activate the p38 MAPK pathway, which may counteract the enhancement induced by this combination. We studied the cytotoxicity of bortezomib, ATO, and ATO + bortezomib with or without inhibiting p38 MAPK, along with associated molecular changes in myeloma cells. The treatment of myeloma cells with ATO + bortezomib induced higher cytotoxicity than either agent alone. This increased cytotoxicity was further synergistically enhanced by inhibiting p38 MAPK. This effect was preserved in the presence of marrow stromal cells designed to simulate the tumor micro-environment and in the CD138+ neoplastic plasma cells directly isolated from myeloma patients. The enhanced cytotoxicity of ATO + bortezomib was associated with augmented STAT3 inhibition and JNK activation, up-regulation of Bim, p21, p27, p53 as well as down-regulation of Bcl-2. Furthermore, the synergistically potentiated apoptosis by p38 MAPK inhibition was associated with the attenuation of ATO + bortezomib-mediated activation of Hsp27 as well as the enhancement of ATO + bortezomib-mediated JNK activation, p53 up-regulation, and Bcl-2 down-regulation. The results suggest the opportunity for using p38 MAPK inhibition to enhance the efficacy of ATO + bortezomib in myeloma.",
keywords = "ATO, Bortezomib, Myeloma, p38 MAPK",
author = "Jianguo Wen and Yongdong Feng and Wanting Huang and Haiyun Chen and Bing Liao and Lawrence Rice and Preti, {Hector A.} and Kamble, {Rammurti T.} and Youli Zu and Ballon, {Douglas J.} and Chang, {Chung Che}",
year = "2010",
month = "1",
day = "1",
doi = "10.1016/j.leukres.2009.05.024",
language = "English (US)",
volume = "34",
pages = "85--92",
journal = "Leukemia Research",
issn = "0145-2126",
publisher = "Elsevier Limited",
number = "1",

}

TY - JOUR

T1 - Enhanced antimyeloma cytotoxicity by the combination of arsenic trioxide and bortezomib is further potentiated by p38 MAPK inhibition

AU - Wen, Jianguo

AU - Feng, Yongdong

AU - Huang, Wanting

AU - Chen, Haiyun

AU - Liao, Bing

AU - Rice, Lawrence

AU - Preti, Hector A.

AU - Kamble, Rammurti T.

AU - Zu, Youli

AU - Ballon, Douglas J.

AU - Chang, Chung Che

PY - 2010/1/1

Y1 - 2010/1/1

N2 - The combination of ATO and bortezomib (ATO + bortezomib) has been recently shown to enhance antimyeloma activity; nevertheless, the mechanisms remained unclear in these studies. However, both bortezomib and ATO have been shown to activate the p38 MAPK pathway, which may counteract the enhancement induced by this combination. We studied the cytotoxicity of bortezomib, ATO, and ATO + bortezomib with or without inhibiting p38 MAPK, along with associated molecular changes in myeloma cells. The treatment of myeloma cells with ATO + bortezomib induced higher cytotoxicity than either agent alone. This increased cytotoxicity was further synergistically enhanced by inhibiting p38 MAPK. This effect was preserved in the presence of marrow stromal cells designed to simulate the tumor micro-environment and in the CD138+ neoplastic plasma cells directly isolated from myeloma patients. The enhanced cytotoxicity of ATO + bortezomib was associated with augmented STAT3 inhibition and JNK activation, up-regulation of Bim, p21, p27, p53 as well as down-regulation of Bcl-2. Furthermore, the synergistically potentiated apoptosis by p38 MAPK inhibition was associated with the attenuation of ATO + bortezomib-mediated activation of Hsp27 as well as the enhancement of ATO + bortezomib-mediated JNK activation, p53 up-regulation, and Bcl-2 down-regulation. The results suggest the opportunity for using p38 MAPK inhibition to enhance the efficacy of ATO + bortezomib in myeloma.

AB - The combination of ATO and bortezomib (ATO + bortezomib) has been recently shown to enhance antimyeloma activity; nevertheless, the mechanisms remained unclear in these studies. However, both bortezomib and ATO have been shown to activate the p38 MAPK pathway, which may counteract the enhancement induced by this combination. We studied the cytotoxicity of bortezomib, ATO, and ATO + bortezomib with or without inhibiting p38 MAPK, along with associated molecular changes in myeloma cells. The treatment of myeloma cells with ATO + bortezomib induced higher cytotoxicity than either agent alone. This increased cytotoxicity was further synergistically enhanced by inhibiting p38 MAPK. This effect was preserved in the presence of marrow stromal cells designed to simulate the tumor micro-environment and in the CD138+ neoplastic plasma cells directly isolated from myeloma patients. The enhanced cytotoxicity of ATO + bortezomib was associated with augmented STAT3 inhibition and JNK activation, up-regulation of Bim, p21, p27, p53 as well as down-regulation of Bcl-2. Furthermore, the synergistically potentiated apoptosis by p38 MAPK inhibition was associated with the attenuation of ATO + bortezomib-mediated activation of Hsp27 as well as the enhancement of ATO + bortezomib-mediated JNK activation, p53 up-regulation, and Bcl-2 down-regulation. The results suggest the opportunity for using p38 MAPK inhibition to enhance the efficacy of ATO + bortezomib in myeloma.

KW - ATO

KW - Bortezomib

KW - Myeloma

KW - p38 MAPK

UR - http://www.scopus.com/inward/record.url?scp=73249129928&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73249129928&partnerID=8YFLogxK

U2 - 10.1016/j.leukres.2009.05.024

DO - 10.1016/j.leukres.2009.05.024

M3 - Article

C2 - 19608275

AN - SCOPUS:73249129928

VL - 34

SP - 85

EP - 92

JO - Leukemia Research

JF - Leukemia Research

SN - 0145-2126

IS - 1

ER -