Journal
MOLECULAR CANCER
Volume 9, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1476-4598-9-112
Keywords
-
Categories
Funding
- National High Technology Research and Development Program of China (863 Program) [2008AA02Z420]
- National Natural Science Fund of China [90713036]
- National Basic Research Program of China (973 Program) [2009CB825506]
Ask authors/readers for more resources
Background: Chronic myelogenous leukemia (CML) is characterized by the chimeric tyrosine kinase Bcr-Abl. Bcr-Abl-T315I is the notorious point mutation that causes resistance to imatinib and the second generation tyrosine kinase inhibitors, leading to poor prognosis. CML blasts have constitutive p65 (RelA NF-kappa B) transcriptional activity, and NF-kappa B may be a potential target for molecular therapies in CML that may also be effective against CML cells with Bcr-Abl-T315I. Results: In this report, we discovered that pristimerin, a quinonemethide triterpenoid isolated from Celastraceae and Hippocrateaceae, inhibited growth and induced apoptosis in CML cells, including the cells harboring Bcr-Abl-T315I mutation. Additionally, pristimerin inhibited the growth of imatinib-resistant Bcr-Abl-T315I xenografts in nude mice. Pristimerin blocked the TNF alpha-induced I kappa B alpha phosphorylation, translocation of p65, and expression of NF-kappa B-regulated genes. Pristimerin inhibited two steps in NF-kappa B signaling: TAK1TIKK and IKKTI kappa B alpha. Pristimerin potently inhibited two pairs of CML cell lines (KBM5 versus KBM5-T315I, 32D-Bcr-Abl versus 32D-Bcr-Abl-T315I) and primary cells from a CML patient with acquired resistance to imatinib. The mRNA and protein levels of Bcr-Abl in imatinib-sensitive (KBM5) or imatinib-resistant (KBM5-T315I) CML cells were reduced after pristimerin treatment. Further, inactivation of Bcr-Abl by imatinib pretreatment did not abrogate the TNFa-induced NF-kappa B activation while silencing p65 by siRNA did not affect the levels of Bcr-Abl, both results together indicating that NF-kappa B inactivation and Bcr-Abl inhibition may be parallel independent pathways. Conclusion: To our knowledge, this is the first report to show that pristimerin is effective in vitro and in vivo against CML cells, including those with the T315I mutation. The mechanisms may involve inhibition of NF-kappa B and Bcr-Abl. We concluded that pristimerin could be a lead compound for further drug development to overcome imatinib resistance in CML patients.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available