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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4415-4423.
Prepublished online as a Blood First Edition Paper on January 30, 2007; DOI 10.1182/blood-2006-09-047076.
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Submitted September 15, 2006
Accepted January 20, 2007
Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation
Yun Dai, Payal Khanna, Shuang Chen, Xin-Yan Pei, Paul Dent, and Steven Grant*
Dept of Medicine, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA, United States
Depts of Pharmacology and Radiation Oncology, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA, United States
Dept of Biochemistry, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA, United States
* Corresponding author; email: stgrant{at}hsc.vcu.edu.
Interactions between UCN-01 and HMG-CoA reductase inhibitors (i.e., statins) have been examined in human leukemia and myeloma cells. Exposure of U937 and U266 cells to minimally toxic concentrations of UCN-01 and various statins (e.g., lovastatin, simvastatin, or fluvastatin) dramatically increased mitochondrial dysfunction, caspase activation, and apoptosis. Comparable effects were observed in other leukemia and myeloma cell lines as well as in primary AML blasts, but not in normal hematopoietic cells. Potentiation of UCN-01 lethality by lovastatin was associated with disruption of Ras prenylation and activation. These events were significantly attenuated by farnesyl pyrophosphate (FPP) but not by geranylgeranyl pyrophosphate (GGPP), implicating perturbations in farnesylation rather than geranylgeranylation in synergistic interactions. Co-exposure to statins and UCN-01 resulted in inactivation of ERK1/2 and Akt, accompanied by JNK activation. U266 cells ectopically expressing JNK1-APF, a dominant-negative JNK1 mutant, displayed significantly reduced susceptibility to lovastatin/UCN-01-mediated lethality. Moreover, transfection of U266 cells with constitutively activated H-Ras (Q61L) attenuated ERK1/2 inactivation and dramatically diminished the lethality of this regimen. Collectively, these findings indicate that HMG-CoA reductase inhibitors act through a Ras farnesylation-associated mechanism to induce signaling perturbations, particularly prevention of Ras and ERK1/2 activation, in UCN-01-treated cells, resulting in the synergistic induction of cell death.
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