Effects of the Tyrosine Kinase Inhibitor Imatinib on Neuroendocrine Tumor Cell Growth

Digestion ◽  
2005 ◽  
Vol 71 (3) ◽  
pp. 131-140 ◽  
Author(s):  
Brigitte Lankat-Buttgereit ◽  
Dieter Hörsch ◽  
Peter Barth ◽  
Rudolf Arnold ◽  
Silke Blöcker ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tyrosine Kinase ◽  
Tumor Cell ◽  
Tyrosine Kinase Inhibitor ◽  
Neuroendocrine Tumor ◽  
Kinase Inhibitor ◽  
Tumor Cell Growth

Activity of the Histone Deacetylase Inhibitor, Vorinostat, Against BCR-ABL Positive Leukemia Cells with Random Mutagenesis and In Combination with Nilotinib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4460-4460
Author(s):  
Seiichi Okabe ◽  
Tetsuzo Tauchi ◽  
Eishi Ashihara ◽  
Shinya Kimura ◽  
Taira Maekawa ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tyrosine Kinase ◽  
Growth Inhibition ◽  
Tyrosine Kinase Inhibitor ◽  
Hdac Inhibitor ◽  
Kinase Inhibitor ◽  
Random Mutagenesis ◽  
Cell Growth Inhibition ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor

Abstract Abstract 4460 The clinical use of imatinib, a specific BCR-ABL tyrosine kinase inhibitor (TKI) is effective in inducing a complete hematological and cytogenetic remission in a high percentage of chronic myeloid leukemia (CML) and Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL) patients. However, imatinib does not efficiently kill leukemic stem cells and is limited by the emergence of resistance due to the point mutations in the BCR-ABL kinase domain. Histone acetyltransferases (HAT) and histone deacetylases (HDAC) control the acetylation of histones and intracellular proteins, and regulate the transcription and function of the proteins. HDAC inhibitor is a structurally diverse class of targeted anti-cancer agent. One of the pan-HDAC inhibitor, vorinostat (suberoylanilide hydroxamic acid: SAHA) is a small-molecule inhibitor of most human class I and class II HDAC, and is reported the efficacy of malignant cells including lymphomas and myeloid malignancies.Therefore, combination therapy using a BCR-ABL tyrosine kinase inhibitor and an HDAC inhibitor, vorinostat may help prevent CML relapse due to BCR-ABL point mutation and may improve their long-term outcome. In this study, we investigated the efficacy of vorinostat by using the Ph-positive leukemia cell line, K562 and Ba/F3 BCR-ABL cell in a random mutagenesis study for BCR-ABL mutation. We first performed a comprehensive drug combination experiment using vorinostat and BCR-ABL tyrosine kinase inhibitor, imatinib or nilotinib. The treatment of imatinib or nilotinib exhibits cell growth inhibition partially against Ba/F3 BCR-ABL cell in a random mutagenesis. We also found the BCR-ABL point mutation such as T315I or M344V after 2 weeks nilotinib treatment by direct sequence analysis. We show that vorinostat potently induced cell growth inhibition of K562 and Ba/F3 BCR-ABL cells in a random mutagenesis in a dose dependent manner. Combined treatment of Ba/F3 BCR-ABL cell in a random mutagenesis with vorinostat and nilotinib or imatinib caused significantly more cytotoxicity than each drug alone by colony assay. We investigated the intracellular signaling of vorinostat. Phosphorylation of BCR-ABL, Crk-L were reduced after vorinostat treatment for 24 hours in a dose dependent manner. Caspase 3 and poly (ADP-ribose) polymerase (PARP) activation were increased after vorinostat treatment. Vorinostat potently enhanced cell growth inhibition of Ba/F3 BCR-ABL point mutants (G250E, Q252H, Y253F, E255K, M294V, T315I, T315A, F317L, F317V, M351T and H396P) compared with Ba/F3 expressing Wt BCR-ABL cells. The protein level of BCR-ABL was reduced after vorinostat treatment. BCR-ABL degradations in BCR-ABL mutant cells were significantly enhanced compared with Ba/F3 Wt BCR-ABL cells. Although long term culture of Ba/F3 BCR-ABL cell in a random mutagenesis with 2μ M vorinostat significantly decreased cell growth, the cells were increased after removal of vorinostat. We found these cells were wild type BCR-ABL by direct sequence analysis. Data from this study suggested that administration of the vorinostat may mediate its effects on BCR-ABL positive cells included BCR-ABL point mutation and enhance cytotoxic effects of nilotinib or imatinib in BCR-ABL mutant cells, and provide information of potential therapeutic relevance. Disclosures: Ohyashiki: Nippon Shinyaku Co., Ltd.: Research Funding.

Radiosensitivity of Tumor Cell Lines after Pretreatment with the EGFR Tyrosine Kinase Inhibitor ZD1839 (Iressa®)

2005 ◽  
Vol 181 (3) ◽  
pp. 197-204 ◽  
Author(s):  
Susanne Burdak-Rothkamm ◽  
Claudia E. Rübe ◽  
Tan Phu Nguyen ◽  
Daniela Ludwig ◽  
Klaus Feldmann ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tumor Cell ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Tumor Cell Lines ◽  
Egfr Tyrosine Kinase Inhibitor ◽  
Egfr Tyrosine Kinase

HHGV678, a Novel Tyrosine Kinase Inhibitor, Inhibits the Cell Growth of Imatinib-Sensitive and Resistant BCR-ABL Positive Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4240-4240
Author(s):  
Lin Qiu ◽  
Xiao-dan Wang ◽  
Fang Ge ◽  
Xiu-li Wang ◽  
Bo-long Zhang ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tyrosine Kinase ◽  
Growth Inhibition ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Point Mutations ◽  
Tyrosine Kinase Domain ◽  
Significant Activity

Abstract Imatinib (IM) is a higherly effective targeted drug for CML. However, some CML patients, especially accelerated and blast crisis phase, often relapse due to drug resistance resulting from the emergence of IM-resistant point mutations within the BCR-ABL tyrosine kinase domain. This stimulates the development of new kinase inhibitors that are able to override resistance to IM. HHGV678 is a novel tyrosine kinase inhibitor and we employed IM-sensitive (K562 and 32Dp210) and resistant (K562R and fifteen 32Dp210 mutants) BCR-ABL+ cell lines to compare HHGV678 with IM on growth inhibition. In addition, synergistic effect of HHGV678 with IM was observed in 32Dp210 and 5 BCR-ABL mutants frequently observed in CML patients. MTT assay results showed that the estimated IC50 value of HHGV678 for K562 and 32Dp210 were 15.5 and 28-fold, for K562R and 15 BCR-ABL mutants, were 1.4–124.0-fold lower than that of IM, indicating that HHGV678 was a more effective than IM against cell growth of IM-sensitive and resistant cells. Using combination index analysis, HHGV678 displayed synergistic growth inhibition when used with IM in BCR-ABL mutants (M244V, Q252H, Y253H, E255K and T315I). HHGV678, combined with IM at their IC50 concentration induced apoptosis 2–5 fold higher than that of HHGV678 alone in BCR-ABL mutants respectively, by annexin-V staining. At the same condition, HHGV6787 resulted in remarkable decrease in CrKL phosphorylation as determined by western blot. We conclude that HHGV678 have significant activity against IM-sensitive and resistant BCR-ABL+ cell, especially when it combined with IM that warrant further investigation in clinical trials.

Inhibition of Tumor Cell Growth by A Specific 6-Phosphofructo-2-kinase Inhibitor,N-Bromoacetylethanolamine Phosphate, and Its Analogues

2000 ◽  
Vol 64 (10) ◽  
pp. 2047-2052 ◽  
Author(s):  
Takafumi HIRATA ◽  
Mitsuaki WATANABE ◽  
Shinji MIURA ◽  
Katsushi IJICHI ◽  
Masashi FUKASAWA ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Kinase Inhibitor ◽  
Tumor Cell Growth ◽  
Bromoacetylethanolamine Phosphate
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