In vitro and in vivo Study of Cell Growth Inhibition of Simvastatin on Chronic Myelogenous Leukemia Cells

Abstract

Background: Statins, a family of 3-hydroxy-3-methylglutaryl CoA (HMG CoA) reductase inhibitors, are being investigated for the therapy and prevention of cancers. Here we aimed to investigate the effects of simvastatin on chronic myelogenous leukemia (CML) cells in vitro and in vivo, and to elucidate the mechanisms. Methods: Cell proliferation and cell cycle were measured after K562 cells were incubated with simvastatin, and differentially expressed genes were determined by oligonucleotide microarray. Changes of 2 genes obtained by oligonucleotide microarray were validated by real-time RT-PCR, and immunohistochemistry was performed to determine expression of proliferating cell nuclear antigen (PCNA). Finally, a xenograft tumor model was constructed to evaluate the effects of simvastatin in vivo. Results: Simvastatin could inhibit K562 cell proliferation, and the inhibition rate was approximately 30% after treatment with 20 µmol/l simvastatin for 48 h. Cell cycle was arrested in G₁ phase, as shown by flow cytometry results. Fifteen downregulated, 9 upregulated cell cycle-related genes and decreased PCNA protein were observed in the presence of simvastatin. Furthermore, simvastatin exhibited impairment of xenograft tumor growth in nude mice and also blocked cell cycle in G₁ phase. Conclusion: Simvastatin can inhibit CML cell proliferation in vitro and in vivo, and its mechanisms might be involved in cell cycle regulation.

Simvastatin modulates the adhesion and growth of hepatocellular carcinoma cells via decrease of integrin expression and ROCK

“…In vitro and in vivo studies showed that statins inhibit tumor cell growth, induce apoptosis, inhibit angiogenesis and impair the metastatic process (16). Although simvastatin has been demonstrated to modulate the pathogenesis of many cancer types by inhibiting tumor cell growth dynamics, data on simvastatin induced effects on hepatocellular carcinoma are sparse (11,17,18). The present in vitro model reveals that simvastatin significantly influenced both the cell growth and adhesion behaviour of human hepatocellular carcinoma cells HepG2 and Huh7.…”

Role of stromal microenvironment in nonpharmacological resistance of CML to imatinib through Lyn/CXCR4 interactions in lipid rafts

“…In CML cells, it has been reported that simvastatin or a combination of lovastatin and interferon-alpha 2b led to cell growth inhibition through cell cycle arrest and caused significant reduction of phosphorylation in tyrosine, serine and threonine protein residues. 43,44 As such, inhibition of cholesterol synthesis, for example by statins, is a potential adjunct to CML therapy. It would be curious to examine whether the encouraging response rates reported in human AML trials combining standard chemotherapy with statins 45 are associated with lipid raft disruption and blockade of CXCR4 signaling.…”

Inhibitory effects of adenovirus mediated COX-2, Akt1 and PIK3R1 shRNA on the growth of malignant tumor cells in vitro and in vivo

“…PCNA expression may be used as a marker of cell proliferation because cells the G1/S phase may be extended when proliferating. In addition, PCNA is essential in nucleic acid metabolism as a component of the DNA replication and repair mechanism (33,34). P53 is an anti-oncogene, and its downregulation or deletion is associated with tumor proliferation and antioncogene inactivation.…”