Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma / N., Raje; T., Hideshima; S., Mukherjee; M., Raab; S., Vallet; S., Chhetri; D., Cirstea; Pozzi, Samantha; C., Mitsiades; M., Rooney; T., Kiziltepe; K., Podar; Y., Okawa; H., Ikeda; R., Carrasco; P. G., Richardson; D., Chauhan; N. C., Munshi; S., Sharma; H., Parikh; B., Chabner; D., Scadden; K. C., Anderson. - In: LEUKEMIA. - ISSN 0887-6924. - ELETTRONICO. - 23:(2009), pp. 961-970.

Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma.

POZZI, Samantha;
2009

Abstract

Cyclin D dysregulation and overexpression is noted in the majority of multiple myeloma (MM) patients, suggesting its critical role in MM pathogenesis. Here, we sought to identify the effects of targeting cyclin D in MM. We first confirmed cyclin D mRNA overexpression in 42 of 64 (65%) patient plasma cells. Silencing cyclin D1 resulted in >50% apoptotic cell death suggesting its validity as a potential therapeutic target. We next evaluated P276-00, a clinical-grade small-molecule cyclin-dependent kinase inhibitor as a way to target the cyclins. P276-00 resulted in dose-dependent cytotoxicity in MM cells. Cell-cycle analysis confirmed either growth arrest or caspase-dependent apoptosis; this was preceded by inhibition of Rb-1 phosphorylation with associated downregulation of a range of cyclins suggesting a regulatory role of P276-00 in cell-cycle progression through broad activity. Proliferative stimuli such as interleukin-6, insulin-like growth factor-1 and bone-marrow stromal cell adherence induced cyclins; P276-00 overcame these growth, survival and drug resistance signals. Because the cyclins are substrates of proteasome degradation, combination studies with bortezomib resulted in synergism. Finally, in vivo efficacy of P276-00 was confirmed in an MM xenograft model. These studies form the basis of an ongoing phase I study in the treatment of relapsed/refractory MM.
23
961
970
Preclinical activity of P276-00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma / N., Raje; T., Hideshima; S., Mukherjee; M., Raab; S., Vallet; S., Chhetri; D., Cirstea; Pozzi, Samantha; C., Mitsiades; M., Rooney; T., Kiziltepe; K., Podar; Y., Okawa; H., Ikeda; R., Carrasco; P. G., Richardson; D., Chauhan; N. C., Munshi; S., Sharma; H., Parikh; B., Chabner; D., Scadden; K. C., Anderson. - In: LEUKEMIA. - ISSN 0887-6924. - ELETTRONICO. - 23:(2009), pp. 961-970.
N., Raje; T., Hideshima; S., Mukherjee; M., Raab; S., Vallet; S., Chhetri; D., Cirstea; Pozzi, Samantha; C., Mitsiades; M., Rooney; T., Kiziltepe; K., Podar; Y., Okawa; H., Ikeda; R., Carrasco; P. G., Richardson; D., Chauhan; N. C., Munshi; S., Sharma; H., Parikh; B., Chabner; D., Scadden; K. C., Anderson
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/708988
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