Pure antiestrogen-induced G1-arrest in myeloma cells results from the reduced kinase activity of cyclin D3/CDK6 complexes whereas apoptosis is mediated by endoplasmic reticulum-dependent caspases

International Journal of Cancer. Journal International Du Cancer
Juliette GauduchonBrigitte Sola

Abstract

Multiple myeloma (MM) is a malignancy characterized by the accumulation of tumoral plasma cells in bone marrow. This disease remains incurable and the development of new therapeutic strategies is urgently required. We have studied the effects of 2 selective estrogen receptor disrupters (SERDs), RU 58668 (RU) and ICI 182,780 (ICI) or pure antiestrogens (AEs) on MM cell lines. Both compounds have antimyeloma activity through either cell cycle arrest or induction of apoptosis. To analyze the molecular mechanisms of SERD action, we choose 2 differently responding cell lines as models. In LP-1 cells, RU blocked cell cycle at the G1 phase. RU treatment induced a rapid decrease of c-Myc, an upregulation of p27(Kip1), and the subsequent decreased activity of cyclin-dependent kinase, CDK6 and associated cyclin D3, impairing the inactivation of the retinoblastoma protein (pRb). In RPMI 8226 cells, RU induced apoptosis by recruiting endoplasmic reticulum- as well as mitochondria-associated caspases. Moreover, RU interfered with the NF-kappaB survival pathway, often deregulated in MM malignancy. Antimyeloma activities were observed in dexamethasone (Dex)- and RU-resistant cells when RU was combined with bortezomib; Dex and bortezomib being...Continue Reading

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Citations

Dec 12, 2012·Leukemia & Lymphoma·Giorgia UrbinatiBrigitte Sola
Jul 30, 2010·Bioorganic & Medicinal Chemistry Letters·Su Hui YangWon-Jea Cho
Jan 5, 2010·Steroids·T S Karin Eisinger-MathasonDeborah A Lannigan

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