Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo

Leukemia
Tony NavasLinda S Higgins

Abstract

Inhibition of p38 kinase blocks the production of tumor-promoting factors in the multiple myeloma (MM) bone marrow microenvironment. Proteasome inhibitors MG132 and bortezomib have been shown to have direct cytotoxic effects on MM cells. We show that a selective inhibitor of p38alpha, SCIO-469, enhances the ability of MG132 and bortezomib to induce the apoptosis of MM cells. Previously, we showed that p38 inhibition with SCIO-469 enhances MM cytotoxicity of bortezomib by inhibiting the transient expression and phosphorylation of Hsp27, a downstream target of p38. Here we show that continued treatment of MM cells with bortezomib leads to a SCIO-469-enhanced downregulation of Hsp27 and to increased MM apoptosis. Furthermore, we show that p38 inhibition enhances the bortezomib-induced MM apoptosis by upregulation of p53 and downregulation of Bcl-X(L) and Mcl-1. In a mouse xenograft plasmacytoma model of MM, we found that inhibiting p38 augments the effects of bortezomib in decreasing MM tumor growth in vivo. Thus, in addition to its role in suppressing an activated MM microenvironment, co-treatment with a p38 inhibitor, such as SCIO-469, may enhance the cytotoxicity of bortezomib by modulating pro-apoptotic and anti-apoptotic fact...Continue Reading

References

Feb 1, 1996·Journal of Leukocyte Biology·J C Lee, P R Young
Aug 22, 2001·Chemistry & Biology·A F Kisselev, A L Goldberg
Oct 23, 2002·Proceedings of the National Academy of Sciences of the United States of America·Nicholas MitsiadesKenneth C Anderson
Jan 3, 2003·Apoptosis : an International Journal on Programmed Cell Death·C G ConcannonA Samali
Mar 5, 2003·Immunological Reviews·Václav Horejsí
Apr 16, 2003·European Journal of Pharmacology·Masayuki NiwaOsamu Kozawa
May 21, 2003·Proceedings of the National Academy of Sciences of the United States of America·Kojo S J Elenitoba-JohnsonMegan S Lim
Jul 9, 2003·Immunological Reviews·Teru HideshimaKenneth C Anderson
Oct 11, 2003·Biochemical and Biophysical Research Communications·Feng-Ting LiuLi Jia
Oct 17, 2003·Genes & Development·Jerry M Adams
Oct 29, 2003·Cancer Control : Journal of the Moffitt Cancer Center·Paul G RichardsonKenneth C Anderson
Nov 25, 2003·Breast Cancer : the Journal of the Japanese Breast Cancer Society·Jun NinomiyaYasuo Morishita
Nov 25, 2003·Oncogene·Suzanne CoryJerry M Adams
Oct 7, 2004·Cell Cycle·Steven Le GouillKenneth C Anderson
Nov 13, 2004·Leukemia·F MagrangeasH Avet-Loiseau

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Citations

Jul 27, 2007·Journal of Cancer Research and Clinical Oncology·Leander GaulRalf Schmidmaier
Mar 20, 2010·Nature Reviews. Cancer·Carlos López-Otín, Tony Hunter
Mar 9, 2007·Leukemia·R MihelicS Lonial
Feb 6, 2010·Annals of Oncology : Official Journal of the European Society for Medical Oncology·N Reddy, M S Czuczman
Jun 6, 2008·Anti-cancer Drugs·Ning ZhangJing Rong Cui
Dec 13, 2006·TheScientificWorldJournal·Janice Jin HwangKenneth C Anderson
Mar 27, 2010·Pigment Cell & Melanoma Research·Angela M KeulingVictor A Tron
Nov 26, 2008·BMC Biochemistry·Dharminder ChauhanKenneth C Anderson
Sep 26, 2008·BMC Genomics·Angelika OehmigHansjürgen Volkmer
Nov 17, 2006·Expert Opinion on Investigational Drugs·Sara BringhenAntonio Palumbo
Oct 27, 2009·Expert Opinion on Investigational Drugs·Hae-Young YongAree Moon
Apr 13, 2012·Cancer Treatment Reviews·Vito LongoFranco Silvestris
Nov 13, 2007·Hematology/oncology Clinics of North America·Constantine S MitsiadesDaniel R Carrasco
Mar 24, 2007·Experimental Hematology·Kenneth C Anderson
May 30, 2008·Liver International : Official Journal of the International Association for the Study of the Liver·Junfang DengShusen Zheng
Jan 5, 2008·British Journal of Haematology·Jianguo WenChung-Che Chang
Aug 17, 2010·Chemico-biological Interactions·Huei-Fang LiuJui-I Chao
Sep 23, 2014·Free Radical Biology & Medicine·Perinur BozaykutBetul Karademir
Aug 12, 2014·Biochemical Society Transactions·Megan Y MurrayKristian M Bowles
Nov 16, 2011·Expert Opinion on Therapeutic Patents·Stefan FischerStefan A Laufer
Mar 21, 2015·Biochemical and Biophysical Research Communications·Shannon SanacoraIvana Vancurova
Jul 17, 2016·Biochemical and Biophysical Research Communications·Yu-Seon KangJang-Seong Kim
Aug 19, 2016·Anti-cancer Drugs·Kang QiXiangYang Chu
Aug 12, 2008·Biochimica Et Biophysica Acta·Megumi IiizumiKounosuke Watabe
Dec 22, 2017·Cancers·Jonas CicenasSigitas Urbonavicius
Jul 29, 2009·Laboratory Investigation; a Journal of Technical Methods and Pathology·Shahab UddinKhawla S Al-Kuraya
May 19, 2006·Toxicological Sciences : an Official Journal of the Society of Toxicology·Angus T De SouzaRoger G Ulrich
Apr 4, 2016·Neurochemical Research·Yueling JinZhensheng Dai
Aug 12, 2014·World Journal of Gastroenterology : WJG·Valentina GrossiCristiano Simone

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