Differential activities of thalidomide and isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells.
Thalidomide has emerged as an effective agent for treating multiple myeloma, however the precise mechanism of action remains unknown. Agents known to target the isoprenoid biosynthetic pathway (IBP) can have cytotoxic effects in myeloma cells. The interactions between thalidomide and IBP inhibitors in human multiple myeloma cells were evaluated. Enhanced cytotoxicity and induction of apoptosis were observed in RPMI-8226 cells. Examination of intracellular levels of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) revealed a wide variance in basal levels and response to IBP inhibitors. These findings provide a mechanism for the differential sensitivity of myeloma cells to pharmacologic manipulation of the IBP.
Holstein
Sarah A
SA
Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, United States.
Tong
Huaxiang
H
Hohl
Raymond J
RJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053898:Biosynthetic Pathways / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D005434:Flow Cytometry; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism*; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism; D013729:Terpenes / Q000037:antagonists & inhibitors*; D013792:Thalidomide / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D013729:Terpenes; D013792:Thalidomide; C004808:farnesyl pyrophosphate; C002963:geranylgeranyl pyrophosphate