Combining simvastatin with the farnesyltransferase inhibitor tipifarnib results in an enhanced cytotoxic effect in a subset of primary CD34+ acute myeloid leukemia samples.
OBJECTIVE
To show whether the inhibitory effects of the cholesterol synthesis inhibitor simvastatin on human CD34(+) acute myeloid leukemia (AML) cells can be further promoted by combining it with the farnesyltransferase inhibitor tipifarnib.


METHODS
Normal CD34(+), AML CD34(+), and CD34(-) sorted subfractions, and AML cell lines (TF-1 and KG1A) were exposed to simvastatin and tipifarnib.


RESULTS
Both simvastatin and tipifarnib showed a cytotoxic effect on AML cell lines, which was additive when used in combination. In primary sorted CD34(+) AML cells, a heterogeneous response pattern was observed upon treatment with simvastatin when analyzing cell survival. A group of normal (n = 12) and abnormal (n = 10) responders were identified within the AML CD34(+) subfraction when compared with normal CD34(+) cells. This distinction was not observed within the AML CD34(-) cell fraction. When the CD34(+) AML cells were exposed to simvastatin and tipifarnib, a significant enhanced inhibitory effect was shown exclusively in the normal AML responder group, whereas the AML CD34(-) cell fractions all showed an enhanced inhibitory effect. The observed heterogeneity in AML responsiveness could not be explained by differences in effects on cholesterol metabolism genes or extracellular signal-regulated kinase phosphorylation in response to simvastatin and tipifarnib treatment.


CONCLUSIONS
The results suggest that combined treatment with statins and farnesyltransferase inhibitors may be beneficial for a subset of AML patients that can be defined by studying the AML CD34(+) fraction.
van der Weide
Karen
K
Department of Hematology, University of Groningen, Groningen, the Netherlands.
de Jonge-Peeters
Susan D P W M
SD
Kuipers
Folkert
F
de Vries
Elisabeth G E
EG
Vellenga
Edo
E
D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D018952:Antigens, CD34 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015363:Quinolones / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D015363:Quinolones; D012333:RNA, Messenger; D019821:Simvastatin; D051231:Farnesyltranstransferase; C402769:tipifarnib