[Doxorubicin, Seliciclib, & Velcade versus MM]
>>Blood. 2005 Apr 12; [Epub ahead of print]
Seliciclib (CYC202 or R-Roscovitine), a small molecule cyclin dependent kinase inhibitor, mediates activity via downregulation of Mcl-1 in multiple myeloma.
Raje N, Kumar S, Hideshima T, Roccaro A, Ishitsuka K, Yasui H, Shiraishi N, Chauhan D, Munshi NC, Green SR, Anderson KC.
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, VA Boston Healthcare System and Harvard Medical School, Boston, MA, USA.
Cyclin dependent kinase (CDK) inhibitors have the potential to induce cell cycle arrest and apoptosis in cancer cells. Seliciclib (CYC202 or R-roscovitine) is a potent CDK inhibitor currently undergoing phase II clinical testing in lung, and B cell malignancies. Here we studied the in vitro cytotoxic activity of seliciclib against multiple myeloma (MM) cells. Our data demonstrates that seliciclib has potent cytotoxicity against MM cells that are both sensitive and resistant to conventional therapy, as well as primary MM patient cells. Cell cycle and western blot analysis confirmed apoptosis. Importantly, seliciclib triggered a rapid downregulation of Mcl-1 transcription and protein expression independent of caspase cleavage. Adherence of MM cells to bone marrow stromal cells (BMSCs) induced increased Mcl-1 expression associated with STAT3 phosphorylation, which was inhibited in a time and dose dependent manner by seliciclib. Furthermore, seliciclib inhibited interleukin-6 (IL-6) transcription and secretion triggered by tumor cell binding to BMSCs. Upregulation of Mcl-1 expression in cocultures was only partially blocked by neutralizing antibody to IL-6, suggesting alternative mechanisms of Mcl-1 modulation by seliciclib. Finally, combination studies of seliciclib with doxorubicin and bortezomib show in vitro synergism, providing the rationale for testing these drug combinations to improve patient outcome in MM.<<
I presume you recognize this compound, Nigel.
Cheers, Tuck |
