Potentiating antitumor effects of a combination therapy with lovastatin and butyrate in the Lewis lung carcinoma model in mice

Abstract

Lovastatin, the drug used for the treatment of hypercholesterolemia, has previously been reported to exert antitumor activity in experimental murine models. Butyrate and butyric acid derivatives are well known to induce differentiation and apoptosis of tumour cells and also have recently gained acceptance as potential anticancer agents. In this study, we examined the antitumor effects of the combination of lovastatin and butyrate or its prodrug tributyrin in vitro and in vivo against a murine Lewis lung carcinoma (3LL). This combination therapy showed synergistic antitumor activity against 3LL cells in vitro. These effects were at least in part due to apoptosis induction that occurred after 12 hr of incubation with lovastatin and butyrate and was preceded by changes in cell cycle distribution of treated cells and expression of p21, p53 and cyclin D1. Remarkably, a systemic treatment of syngeneic mice inoculated with 3LL cells with both drugs resulted in significant tumour growth retardation.

Butyrate Increases Apoptosis Induced by Different Antineoplastic Drugs in Monocytic Leukemia Cells

“…The promising use of butyrate as an anticancer adjuvant is also suggested by some experiments in mice. Giermasz et al [17] showed that the combination of butyrate and lovastatin resulted in a strongly potentiated tumor growth retardation in melanoma-bearing mice. Another study by Bras-Gonçalves et al [12] demonstrated that treatment with butyrate in combination with 5-fluorouracil resulted in a decrease in tumor volume and an increase in survival of mice with colorectal cancer xenografts.…”

Ciglitazone, an agonist of peroxisome proliferator-activated receptor γ, exerts potentiated cytostatic/cytotoxic effects against tumor cells when combined with lovastatin

“…Moreover, several recent observations indicate that activation of PPAR-γ is associated with inhibition of phosphatidylinositol 3'-kinase (PI3K)/Akt activity, an effect that might be directly related to thiazolidinedione-induced stimulation of PTEN expression (31)(32)(33). Similarly, statins were shown to interfere with cell cycle progression by affecting the expression levels and activity of CDKs and their inhibitors (34)(35)(36). We observed that although ciglitazone at a dose of 25 μM did not affect expression levels of p21…”

Threes Company: Regulation of Cell Fate by Statins

“…Further reported changes in the molecular machinery of the cell cycle upon in vitro exposure to statins include downregulation of H-ras [17,46], p38 and MAPK activity [47,48], PCNA [46,48] and cyclin A [23]; conversely, p53 [32,42,46] and mitosin (a centromere-associated protein) [27] are induced. H-ras suppression and p53 induction have also been documented upon in vivo statin treatment [46], where downstream effectors of the classical MAPK (c-fos) and p38 / JNK (c-jun) signalling pathways are also downregulated [44].…”

“…At the molecular level, statin-mediated cell cycle arrest is often preceded by upregulation of p21 Cip1 [7, 17, 22, 26, 30-32, 36, 41, 42] and p27 Kip1 [23,24,30,31,34,36,[42][43][44]; with concurrent suppression of cyclins D [23,31,32,37,45], E [23,24,34,37], CDKs 2 [23,24,37,41], 4, 6 [24,31,41] and a reduction in phosphorylated pRb [7,23]. However, cyclin [23,24,31], CDK [23,31], p21 Cip1 [23,30,40,42] and p27 Kip1 [30,34] modulation are also individually dispensable for statin-induced cell cycle arrest.…”