Abstract
Multiple myeloma (MM) is a malignancy of antibody-producing plasma cells with genomic instability and genetic abnormality as its two hallmarks. Therefore, DNA damage is pervasive in MM cells, which indicates irregular DNA damage response (DDR) pathway. In this study, we demonstrated that LT-171-861, a multiple kinase inhibitor, could inhibit proliferation and induce apoptosis in MM cells. LT-171-861 promoted DDR pathway and triggered DNA damage through impeding the process of homologous recombination in double strand breaks, rather than directly elevating ROS level in MM cells. Mechanism research revealed that Pim2 inhibition was responsible for LT-171-861-indcued DNA damage and cell apoptosis. LT-171-861 mainly suppressed Pim2 kinase activity and reduced the expression of its phosphorylated substrates, such as 4EBP1 and BAD. Moreover, Olaparib, a PARP inhibitor, could enhance the antitumor effect of LT-171-861 in suppressing tumor growth in MM xenografted nude mice. Taken together, our results demonstrated that LT-171-861 showed a promising therapeutic potential for MM and had an additional lethal effect with PARP inhibitors.
References
Feb 24, 1989·Cell·M van LohuizenA Berns
Feb 3, 1997·The EMBO Journal·M J O'ConnellP Nurse
Mar 21, 1998·Genes & Development·A C GingrasN Hay
Jun 13, 2000·Oncogene·T HiranoM Hibi
Sep 5, 2003·The Journal of Biological Chemistry·Bin YanMichael Lilly
Jul 21, 2004·The Prostate·Alexander ValdmanLars Egevad
Jun 21, 2008·Science·Akiko SekiGuowei Fang
Jul 11, 2008·Nature·Libor MacůrekRené H Medema
Oct 13, 2009·Pathology Oncology Research : POR·Ke RenJianping Gong
Feb 11, 2010·Haematologica·Laurent BraultJürg Schwaller
Jul 9, 2010·Lancet·Andrew TuttJames Carmichael
Apr 9, 2011·Leukemia·J AsanoM Abe
May 14, 2011·Leukemia·D K WaltersD F Jelinek
Oct 16, 2012·Acta Pharmacologica Sinica·Li-jing YangGuo-hui Cui
Jul 3, 2013·Blood·Jing LuPablo D Garcia
May 3, 2014·Leukemia·M HiasaM Abe
Dec 30, 2014·Lancet·Christoph RölligMartin Bornhäuser
Nov 19, 2015·BioMed Research International·Antonia CagnettaMichele Cea
Apr 2, 2016·Nature Reviews. Molecular Cell Biology·Per HydbringPiotr Sicinski
Aug 27, 2016·Blood Cancer Journal·J RamachandranN Raje
Dec 23, 2016·Leukemia·J R NairK P Lee
Jan 27, 2017·The Journal of Cell Biology·Jia QuMin Huang
Jan 28, 2017·Nature Reviews. Cancer·Tobias Otto, Piotr Sicinski
Jun 6, 2017·Frontiers in Oncology·Ana Belén Herrero, Norma Carmen Gutiérrez
Jan 23, 2018·Journal of Medicinal Chemistry·Yue WangTao Lu
Jun 9, 2018·Drug Design, Development and Therapy·Domenica LorussoFrancesco Raspagliesi
Feb 23, 2020·Haematologica·Daniele CaraccioloPierfrancesco Tassone
Jul 28, 2020·Nature Communications·Hyoung KimFiona Simpkins
Jan 5, 2021·Theranostics·Zhou YuNa Lu