Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin

Kuroda, Junya; Kamitsuji, Yuri; Kimura, Shinya; Ashihara, Eishi; Kawata, Eri; Nakagawa, Yoko; Takeuichi, Miki; Murotani, Yoshihide; Yokota, Asumi; Tanaka, Ray; Andreeff, Michael; Taniwaki, Masafumi; Maekawa, Taira

doi:10.1007/s12185-008-0081-8

Cited by 55 publications

(52 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, our data showed that the levels of Bim were unperturbed after HHT treatment (Figs. 3C and 2D), which are consistent with the studies described by Kuroda et al (40) who showed that HHT exerts a minimal effect on Bim expression in myeloma cells. These data from us and others argue against the possibility that HHT-induced apoptosis stems from upregulation of Bim.…”

Section: Hht Induces Apoptosis In D816v Kit-expressing Cells and Decrsupporting

confidence: 91%

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Jin

Lu²,

Cao³

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Gain-of-function mutations of the receptor tyrosine kinase KIT play a critical role in the pathogenesis of systemic mastocytosis (SM) and gastrointestinal stromal tumors. The various juxtamembrane type of KIT mutations, including V560G, are found in 60% to 70% of patients with gastrointestinal stromal tumors; loop mutant D816V, which exists in ∼80% of SM patients, is completely resistant to imatinib. In the present study, we hypothesized that homoharringtonine (HHT), a protein synthesis inhibitor, would decrease the level of KIT protein by inhibiting translation, resulting in a decreased level of phospho-KIT and abrogating its constitutive downstream signaling. Imatinib-sensitive HMC-1.1 cells harboring the mutation V560G in the juxtamembrane domain of KIT, imatinib-resistant HMC-1.2 cells harboring both V560G and D816V mutations, and murine P815 cells were treated with HHT and analyzed in terms of growth, apoptosis, and signal transduction. The in vivo antitumor activity was evaluated by using the murine mast cell leukemia model. Our results indicated that HHT effectively inhibited the growth and induced apoptosis in cells bearing both V560G and D816V or D814Y KIT. Additionally, HHT inhibited the KIT-dependent phosphorylation of downstream signaling molecules Akt, signal transducer and activator of transcription 3 and 5, and extracellular signal-regulated kinase 1/2. Furthermore, HHT significantly prolonged the survival duration of mice with aggressive SM or mast cell leukemia by inhibiting the expansion and infiltration of imatinib-resistant mast tumor cells harboring imatinib-resistant D814Y KIT. Collectively, we show that HHT circumvents D816V KITelicited imatinib resistance. Our findings warrant a clinical trial of HHT in patients with SM harboring D816V or D814Y KIT. Mol Cancer Ther; 9(1); 211-23. ©2010 AACR.

show abstract

Section: Hht Induces Apoptosis In D816v Kit-expressing Cells and Decrsupporting

confidence: 91%

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Jin

Lu²,

Cao³

et al. 2010

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…17 The IM9 subline with lower sensitivity to bortezomib (Bor) (IM9-Bor), established by Dr Terui Y, was maintained with 20 nM Bor. The recombinant hGal9, which is highly stable against proteolysis, was synthesized by Galpharma (Kagawa, Japan).…”

Section: Cell Lines and Reagentsmentioning

confidence: 99%

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways

et al. 2010

View full text Add to dashboard Cite

Galectins constitute a family of lectins that specifically exhibit the affinity for b-galactosides and modulate various biological events. Galectin-9 is a tandem-repeat type galectin with two carbohydrate recognition domains and has recently been shown to have an anti-proliferative effect on cancer cells. We investigated the effect of recombinant protease-resistant galectin-9 (hGal9) on multiple myeloma (MM). In vitro, hGal9 inhibited the cell proliferation of five myeloma cell lines examined, including a bortezomib-resistant subcell line, with IC 50 between 75.1 and 280.0 nM, and this effect was mediated by the induction of apoptosis with the activation of caspase-8, -9, and -3. hGal9-activated Jun NH 2 -terminal kinase (JNK) and p38 MAPK signaling pathways followed by H2AX phosphorylation. Importantly, the inhibition of either JNK or p38 MAPK partly inhibited the anti-proliferative effect of hGal9, indicating the crucial role of these pathways in the anti-MM effect of hGal9. hGal9 also induced cell death in patient-derived myeloma cells, some with poor-risk factors, such as chromosomal deletion of 13q or translocation t(4;14)(p16;q32). Finally, hGal9 potently inhibited the growth of human myeloma cells xenografted in nude mice. These suggest that hGal9 is a new therapeutic target for MM that may overcome resistance to conventional chemotherapy.

show abstract

“…53 However, other reports have indicated that the proapoptotic activity of HHT may involve not only the activation of caspase-9, caspase-3, and PARP but also the activation of caspase-8, thus involving both intrinsic and extrinsic apoptotic pathways, as demonstrated in human myeloma cell lines and tumor cells from patients with recurrent/refractory multiple myeloma. 54,55 These discrepancies in the mechanism of action of HHT may relate to differences between omacetaxine and HHT as well as the use of different cell types in different reports. Mcl-1 down-regulation may result in an increase in free BH3-only proteins, such as Bim, tBid, Bik, and Puma in addition to reducing the levels of beta-catenin and X-linked inhibitor of apoptosis (XIAP) proteins.…”

Section: Phase 2 Studies Of Intravenous Hht In CMLmentioning

confidence: 99%

Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009

Quintás‐Cardama

Kantarjian²,

Cortés

2009

Cancer

View full text Add to dashboard Cite

Homoharringtonine (HHT) is a natural alkaloid that is obtained from various Cephalotaxus species. The mechanism of action by which HHT exerts its antitumor activity is through inhibition of protein synthesis and promotion of apoptosis. In the 1990s, HHT proved to be significantly active as salvage therapy for patients with chronic myeloid leukemia (CML) after failure on interferon-a therapy. However, the remarkable success of imatinib mesylate in the treatment of CML relegated HHT to oblivion. The development of omacetaxine mepesuccinate, a subcutaneously bioavailable semisynthetic form of HHT, and its activity in imatinib-resistant CML has established this agent for the second time as a valuable option in the management of this disease. Preliminary results appear to support the use of this agent for patients who have imatinibresistant CML, including those who carry the tyrosine kinase inhibitor-insensitive mutation that exchanges the amino acids threonine and isoleucine at position 315 (the T315I mutation). In this article, the authors discuss the current data on omacetaxine and the prospects of this agent to be integrated into the state-ofthe-art treatment algorithms for CML.

show abstract

Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and β-catenin

Cited by 55 publications

References 50 publications

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

The Antitumor Activity of Homoharringtonine against Human Mast Cells Harboring the KIT D816V Mutation

Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways

Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009

Contact Info

Product

Resources

About