Douglas J Ballon

Publications (2)7.3 Total impact

• Article: 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
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  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.
  Leukemia research 08/2009; 34(1):85-92. · 2.36 Impact Factor
• Article: P38 MAPK inhibition enhancing ATO-induced cytotoxicity against multiple myeloma cells.

  Jianguo Wen, Haiyun Y Cheng, Yongdong Feng, Lawrence Rice, Shangfeng Liu, Albert Mo, James Huang, Youli Zu, Douglas J Ballon, Chung-Che Chang
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  ABSTRACT: The resistance to arsenic trioxide (ATO) treatment is relatively common (55-80%) in multiple myeloma patients. This study found that ATO at clinically achievable concentrations (2-7 mumol/l) activated p38 mitogen-activated protein kinase (MAPK) in both myeloma cell lines and primary myeloma cells, a finding not previously well-documented in myeloma cells. Inhibition of p38 MAPK activation by pharmacological inhibitors (SB203580) or downregulation of p38 MAPK by siRNA significantly increased the apoptosis and/or growth inhibition induced by ATO treatment in myeloma cells. Combination of ATO and p38 MAPK inhibition abolished the interleukin-6 enhanced protection of myeloma cells against ATO treatment. The ATO-resistant cell line developed in our laboratory showed an increase in p38 MAPK activation. The increase of apoptosis by the combination of ATO and SB203580 was accompanied by the activation of caspase-9 and caspase-8 suggesting that both extrinsic and intrinsic apoptotic pathways are involved. Additionally, the p38 MAPK activation by ATO was associated with increased phosphorylation and upregulated expression of Heat shock protein 27. These results suggest that ATO-induced p38 MAPK activation plays an important role in the resistance to ATO in myeloma cells and that p38 MAPK inhibition may overcome resistance to ATO treatment in myeloma patients.
  British Journal of Haematology 02/2008; 140(2):169-80. · 4.94 Impact Factor