Statins Induce Lethal Effects in Acute Myeloblastic Leukemia [corrected] Cells Within 72 Hours

Overview

Journal Leuk Lymphoma

Specialties Hematology
Oncology

Date 2008 Jan 31

PMID 18231920

Citations 12

Authors

Lillian P Burke

Cynthia A Kukoly

Affiliations

Soon will be listed here.

Abstract

HMG-CoA Reductase inhibitors (statins) induce apoptosis in acute myeloid leukemia (AML) cells in vitro; however, the concentrations associated with cell death in AML cells are higher than those clinically tolerated during prolonged therapy. We therefore wished to determine whether short exposures to lovastatin might induce cell death in AML cells at clinically attainable concentrations. The time and concentration dependence of HL60 and U937 cells was determined and showed that cell death was delayed. IC(50) values and IC(90) values determined on day 6 suggested that the sensitivity of AML cells to statins may occur at lower concentrations than previously reported. After 72 h, mevalonate did not rescue AML cells from cytotoxic concentrations of statins, suggesting that, although cell death was delayed, lovastatin induced lethal effects within 72 h. In conjunction with previously reported Phase I studies, the data presented here suggest that the high-dose, short course statins may be useful for the treatment of patients with AML.

Citing Articles

Statins markedly potentiate aminopeptidase inhibitor activity against (drug-resistant) human acute myeloid leukemia cells.

Jansen G, Al M, Assaraf Y, Kammerer S, Van Meerloo J, Ossenkoppele G Cancer Drug Resist. 2023; 6(3):430-446.

PMID: 37842233 PMC: 10571057. DOI: 10.20517/cdr.2023.20.

Statin use in myelodysplastic syndromes is associated with a better survival and decreased progression to leukemia.

Afzal A, Fiala M, Jacoby M, Walter M Blood Adv. 2023; 7(15):3838-3841.

PMID: 37042968 PMC: 10393730. DOI: 10.1182/bloodadvances.2023009818.

Use of statins and risk of myeloproliferative neoplasms: a Danish nationwide case-control study.

Kristensen D, Kisbye Ovlisen A, Jakobsen L, Severinsen M, Hannig L, Starklint J Blood Adv. 2023; 7(14):3450-3457.

PMID: 36877642 PMC: 10362262. DOI: 10.1182/bloodadvances.2023009784.

Targeting -Mutated Acute Myeloid Leukemia: Research and Clinical Developments.

Granowicz E, Jonas B Onco Targets Ther. 2022; 15:423-436.

PMID: 35479302 PMC: 9037178. DOI: 10.2147/OTT.S265637.

Crosstalk between Statins and Cancer Prevention and Therapy: An Update.

Grabarek B, Boron D, Morawiec E, Michalski P, Palazzo-Michalska V, Pach L Pharmaceuticals (Basel). 2021; 14(12).

PMID: 34959621 PMC: 8704600. DOI: 10.3390/ph14121220.

References

Pallis M, Turzanski J, Higashi Y, Russell N . P-glycoprotein in acute myeloid leukaemia: therapeutic implications of its association with both a multidrug-resistant and an apoptosis-resistant phenotype. Leuk Lymphoma. 2002; 43(6):1221-8. DOI: 10.1080/10428190290026277. View

Poynter J, Gruber S, Higgins P, Almog R, Bonner J, Rennert H . Statins and the risk of colorectal cancer. N Engl J Med. 2005; 352(21):2184-92. DOI: 10.1056/NEJMoa043792. View

Dimitroulakos J, Nohynek D, Backway K, Hedley D, Yeger H, Freedman M . Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: A potential therapeutic approach. Blood. 1999; 93(4):1308-18. View

Diamond A, Jaffe D, Murray J, Safa A, Samuels B, Hatfield D . Lovastatin effects on human breast carcinoma cells. Differential toxicity of an adriamycin-resistant derivative and influence on selenocysteine tRNAS. Biochem Mol Biol Int. 1996; 38(2):345-55. View

Holstein S, Knapp H, Clamon G, Murry D, Hohl R . Pharmacodynamic effects of high dose lovastatin in subjects with advanced malignancies. Cancer Chemother Pharmacol. 2005; 57(2):155-64. DOI: 10.1007/s00280-005-0013-8. View

Thibault A, Samid D, Tompkins A, Figg W, Cooper M, Hohl R . Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res. 1996; 2(3):483-91. View

Maksumova L, Ohnishi K, Muratkhodjaev F, Zhang W, Pan L, Takeshita A . Increased sensitivity of multidrug-resistant myeloid leukemia cell lines to lovastatin. Leukemia. 2000; 14(8):1444-50. DOI: 10.1038/sj.leu.2401856. View

Xia Z, Tan M, Wong W, Dimitroulakos J, Minden M, Penn L . Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells. Leukemia. 2001; 15(9):1398-407. DOI: 10.1038/sj.leu.2402196. View

Knox J, Siu L, Chen E, Dimitroulakos J, Kamel-Reid S, Moore M . A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Eur J Cancer. 2005; 41(4):523-30. DOI: 10.1016/j.ejca.2004.12.013. View

10.

Grundy S, Cleeman J, Merz C, Brewer Jr H, Clark L, Hunninghake D . Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004; 44(3):720-32. DOI: 10.1016/j.jacc.2004.07.001. View

11.

Holstein S, Hohl R . Interaction of cytosine arabinoside and lovastatin in human leukemia cells. Leuk Res. 2001; 25(8):651-60. DOI: 10.1016/s0145-2126(00)00162-4. View

12.

Clutterbuck R, Millar B, Powles R, Newman A, Catovsky D, Jarman M . Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice. Br J Haematol. 1998; 102(2):522-7. DOI: 10.1046/j.1365-2141.1998.00783.x. View

13.

Dale K, Coleman C, Henyan N, Kluger J, White C . Statins and cancer risk: a meta-analysis. JAMA. 2006; 295(1):74-80. DOI: 10.1001/jama.295.1.74. View

14.

Wong W, Dimitroulakos J, Minden M, Penn L . HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia. 2002; 16(4):508-19. DOI: 10.1038/sj.leu.2402476. View

15.

Li H, Appelbaum F, Willman C, Zager R, Banker D . Cholesterol-modulating agents kill acute myeloid leukemia cells and sensitize them to therapeutics by blocking adaptive cholesterol responses. Blood. 2002; 101(9):3628-34. DOI: 10.1182/blood-2002-07-2283. View

16.

Lishner M, Elis A, Fabian I . Effect of simvastatin alone and in combination with cytosine arabinoside on the proliferation of myeloid leukemia cell lines. J Investig Med. 2001; 49(4):319-24. DOI: 10.2310/6650.2001.33896. View

17.

Holmberg M, Sandberg C, Nygren P, Larsson R . Effects of lovastatin on a human myeloma cell line: increased sensitivity of a multidrug-resistant subline that expresses the 170 kDa P-glycoprotein. Anticancer Drugs. 1994; 5(5):598-600. DOI: 10.1097/00001813-199410000-00012. View

18.

Dimitroulakos J, Yeger H . HMG-CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: lovastatin specifically targets P-glycoprotein-expressing cells. Nat Med. 1996; 2(3):326-33. DOI: 10.1038/nm0396-326. View

19.

Zhong W, Wang C, Chang T, Lee W . Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis. Endocrinology. 2003; 144(9):3852-9. DOI: 10.1210/en.2003-0098. View

20.

Spek E, Bloem A, van de Donk N, Bogers L, van der Griend R, Kramer M . Dose-finding study of high-dose simvastatin combined with standard chemotherapy in patients with relapsed or refractory myeloma or lymphoma. Haematologica. 2006; 91(4):542-5. View