JOURNAL ARTICLE

The insulin-like growth factor-I receptor inhibitor NVP-AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells

Patricia Maiso, Enrique M Ocio, Mercedes Garayoa, Juan C Montero, Francesco Hofmann, Carlos García-Echeverría, Johann Zimmermann, Atanasio Pandiella, Jesús F San Miguel
British Journal of Haematology 2008, 141 (4): 470-82
18341634
Multiple myeloma (MM) is a B-cell malignancy characterized by accumulation of monoclonal plasma cells in the bone marrow (BM). Despite recent advances in the treatment, MM represents an incurable disease for which development of new therapies is required. We report the antimyeloma effect of NVP-AEW541, a small molecule that belongs to the pyrrolo[2,3-d]pyrimidine class, identified as a selective inhibitor of the insulin-like growth factor-I receptor (IGF-IR) in vitro kinase activity. NVP-AEW541 had a potent cytotoxic effect on fresh cells and in a murine MM model. NVP-AEW541 partially abrogated the proliferative advantage conferred by the coculture with BM stromal cells and the presence of growth factors produced by the BM microenvironment. In addition, NVP-AEW541 potentiated the action of drugs, such as bortezomib, lenalidomide, dexamethasone or melphalan. Moreover the triple combination of NVP-AEW541, dexamethasone and bortezomib resulted in a significant increase in growth inhibition. Mechanistic studies indicated that NVP-AEW541 provoked a marked cell cycle blockade accompanied by pRb downregulation. Interestingly, NVP-AEW541 increased the levels of p27 associated with a reduction in the CDK2 activity. Finally, NVP-AEW541 induced cell death through caspase-dependent and -independent mechanisms. All these data, suggest the potential effect of IGF-IR kinase inhibitors as therapeutic agents for MM patients.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
18341634
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"