Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs

Kumar, Santosh; Raje, Noopur; Hideshima, Teru; Ishitsuka, Kenji; Roccaro, Aldo M.; Shiraishi, Norihiko; Hamasaki, Makoto; Munshi, Nikhil C.; Richardson, Paul G.; Figg, William D.; Anderson, Kenneth C.

doi:10.1038/sj.leu.2403776

Cited by 35 publications

(41 citation statements)

References 16 publications

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“…3O). This recovery fits with previous reports suggesting CPS49 is active in vitro for 12-18 h (27). Identical results were obtained by using cultures of rat aortic rings (Fig.…”

Section: Defects In Vascular Development Occur Upstream Of Changes Insupporting

confidence: 79%

Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation

Therapontos

Erskine

Gardner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

230

319

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Thalidomide is a potent teratogen that induces a range of birth defects, most commonly of the developing limbs. The mechanisms underpinning the teratogenic effects of thalidomide are unclear. Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects. These results explain both the timing and relative tissue specificity of thalidomide embryopathy and have significant implications for its use as a therapeutic agent.blood vessels ͉ chick limb development ͉ thalidomide analog ͉ angiogensis ͉ zebrafish

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“…3O). This recovery fits with previous reports suggesting CPS49 is active in vitro for 12-18 h (27). Identical results were obtained by using cultures of rat aortic rings (Fig.…”

Section: Defects In Vascular Development Occur Upstream Of Changes Insupporting

confidence: 79%

Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation

Therapontos

Erskine

Gardner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

230

319

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“…In addition to IL-6 the bone marrow microenvironment is known to produce a myriad of other growth factors and cytokines, which may obviate a requirement for IL-6 but may also signal in a JAK-dependent manner. Indeed several novel compounds, which have been used successfully in the treatment of myeloma (notably thalidomide), may in part function by inhibiting cytokine signaling leading to a reduction in JAK-STAT3 activity (49). Finally, we examined the effects of P6 on the growth of primary myeloma samples and determined that P6 had a significant effect on cell viability in the majority of the samples.…”

Section: Discussionmentioning

confidence: 99%

Pyridone 6, A Pan-Janus–Activated Kinase Inhibitor, Induces Growth Inhibition of Multiple Myeloma Cells

et al. 2006

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Interleukin-6 (IL-6) and the subsequent Janus-activated kinase (JAK)-dependent signaling pathways play a critical role in the pathogenesis of multiple myeloma. Here, we compared the sensitivity and specificity of a novel pan-JAK inhibitor, tetracyclic pyridone 6 (P6), with that of AG490 in a panel of myeloma-derived cell lines. P6 induced growth arrest and subsequent apoptosis of the IL-6-dependent hybridoma and myeloma-derived cell lines (B9 and INA-6) grown either in IL-6-containing medium or in the presence of bone marrowderived stromal cells (BMSC) using much lower concentrations of drug and with significantly faster kinetics than AG490.

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“…For the experiments, BMSCs were incubated in 96-well culture plates (approximately 5000-10 000 BMSCs/well) for 24 h or grown to confluence in six-well plates as required for individual experiments. 19,20 …”

Section: Cell Lines Patient Cells and Marrow Stromal Cellsmentioning

confidence: 99%

“…Blots were stripped and reprobed with antiactin antibody (Abcam, Cambridge, UK) to confirm equivalent protein loading and transfer. 19,20 For the caspase inhibition experiments, cells were incubated for 1 h with 20 mM ZVADfmk (Calbiochem), followed by treatment with ABT-737 (10 mM) for the times indicated in the respective experiments. For each experiment caspase inhibition was confirmed by immunoblotting for caspase 3 and poly(ADP-ribose) polymerase (PARP).…”

Section: Immunoblottingmentioning

confidence: 99%

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ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells

et al. 2007

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Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs

Cited by 35 publications

References 16 publications

Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation

Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation

Pyridone 6, A Pan-Janus–Activated Kinase Inhibitor, Induces Growth Inhibition of Multiple Myeloma Cells

ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells

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