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Anthelmintic niclosamide suppresses transcription of BCR-ABL fusion oncogene via disabling Sp1 and induces apoptosis in imatinib-resistant CML cells harboring T315I mutant.

ABSTRACT: Tyrosine kinase BCR-ABL fusion protein is the driver in patients with chronic myeloid leukemia (CML). The gate-keeper mutation T315I is the most challenging mutant due to its resistance to most tyrosine kinase inhibitors (TKIs). The third generation TKI ponatinib is the only effective TKI to treat CML patients harboring T315I-BCR-ABL mutation, but with high rate of major arterial thrombotic events. Alternative strategies to specifically target T315I-BCR-ABL are needed for the treatment of CML patients harboring such a mutation. Given that Sp1 is a fundamental transcriptional factor to positively regulate WT-BCR-ABL fusion oncogene, the purpose of this investigation was aimed at evaluating the anti-tumor activity and the underlying mechanism in terms of Sp1 regulational effect on the transcription of T315I-BCR-ABL fusion oncogene. Like in WT-BCR-ABL, we identified enrichment of Sp1 on the promoter of T315I-BCR-ABL fusion gene. Treatment of WT- and T315I-BCR-ABL-expressing CML cells by niclosamide diminished such an enrichment of Sp1, and decreased WT- and T315I-BCR-ABL transcription and its downstream signaling molecules such as STAT5 and Akt. Further, niclosamide significantly inhibited the proliferation and induced apoptosis through intrinsic pathway. The in vivo efficacy validation of p-niclosamide, a water soluble derivative of niclosamide, showed that p-niclosamide significantly inhibited the tumor burden of nude mice subcutaneously bearing T315I-BCR-ABL-expressing CML cells, and prolonged the survival of allografted leukemic mice harboring BaF3-T315I-BCR-ABL. We conclude that niclosamide is active against T315I-BCR-ABL-expressing cells, and may be a promising agent for CML patients regardless of T315I mutation status.

SUBMITTER: Jin B

PROVIDER: S-EPMC5833368 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundChronic 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-kappaB) transcriptional activity, and NF-kappaB may be a potential target for molecular therapies in CML that may also be effective against CML cells with Bcr-Abl-T315I.ResultsIn 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 TNFalpha-induced IkappaBalpha phosphorylation, translocation of p65, and expression of NF-kappaB-regulated genes. Pristimerin inhibited two steps in NF-kappaB signaling: TAK1TauIKK and IKKTauIkappaBalpha. 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 TNFalpha-induced NF-kappaB activation while silencing p65 by siRNA did not affect the levels of Bcr-Abl, both results together indicating that NF-kappaB inactivation and Bcr-Abl inhibition may be parallel independent pathways.ConclusionTo 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-kappaB and Bcr-Abl. We concluded that pristimerin could be a lead compound for further drug development to overcome imatinib resistance in CML patients.

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Anthelmintic niclosamide suppresses transcription of BCR-ABL fusion oncogene via disabling Sp1 and induces apoptosis in imatinib-resistant CML cells harboring T315I mutant.

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