Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, potentiate the anti-angiogenic effects of bevacizumab by suppressing angiopoietin2, BiP, and Hsp90α in human colorectal cancer

Abstract

Background:Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are commonly prescribed because of their therapeutic and preventive effects on cardiovascular diseases. Even though they have been occasionally reported to have antitumour activity, it is unknown whether statins have anti-angiogenic effect in human colorectal cancer (CRC).Methods:A total of 11 human CRC cell lines were used to test the effects of bevacizumab, statins, and bevacizumab plus statins on human umbilical vein endothelial cell (HUVEC) viability and invasion in vitro. To determine the molecular mechanism of statins as anti-angiogenic agents, we performed an angiogenesis antibody array and proteomics analysis and confirmed the results using immunoblot assay, HUVEC invasion rescue assay, and siRNA assay. The antitumoural effects of bevacizumab and statins were evaluated in xenograft models.Results:A conventional dose of statins (simvastatin 0.2 μM, lovastatin 0.4 μM, atorvastatin 0.1 μM, and pravastatin 0.4 μM) in combination with bevacizumab directly reduced the cell viability, migration, invasion, and tube formation of HUVECs. The culture media of the CRC cells treated with bevacizumab or statins were also found to inhibit HUVEC invasion by suppressing angiogenic mediators, such as angiopoietin2, binding immunoglobulin protein (BiP), and Hsp90α. The combined treatment with bevacizumab and simvastatin significantly reduced the growth and metastases of xenograft tumours compared with treatment with bevacizumab alone.Conclusions:The addition of simvastatin at a dose used in patients with cardiovascular diseases (40–80 mg once daily) may potentiate the anti-angiogenic effects of bevacizumab on CRC by suppressing angiopoietin2, BiP, and Hsp90α in cancer cells. A clinical trial of simvastatin in combination with bevacizumab in patients with CRC is needed.

Enhanced Anticancer Activity of PF-04691502, a Dual PI3K/mTOR Inhibitor, in Combination With VEGF siRNA Against Non–small-cell Lung Cancer

“…56 Previous reports showed that VEGF enhanced the ability of HUVEC to organize into tubular networks on Matrigel 57 and that tube formation is reduced by VEGF inhibitors or siRNA. 58,59 PF0 (100 nmol/l) treatment showed a nonsignificant ( P < 0.05) decrease in tube segments length compared to control ( Figure 6a , e ). Previous studies showed that higher concentrations of PI3K/mTOR dual inhibitors (1 µmol/l) significantly ( P > 0.05) decreased HUVEC tube formation and tumor angiogenesis.…”

Synergistic Effect of Simvastatin Plus Radiation in Gastric Cancer and Colorectal Cancer: Implications of BIRC5 and Connective Tissue Growth Factor

“…In previous studies, we demonstrated anticancer properties of simvastatin in GC and CRC both in vitro and in vivo (30)(31)(32)(33)(34). However, its role as a potential ionizing radiation sensitizer or adjunct to radiation has not been investigated in either GC or CRC.…”

Lovastatin‐mediated MCF‐7 cancer cell death involves LKB1‐AMPK‐p38MAPK‐p53‐survivin signalling cascade

“…16,17 Beyond lipid-lowering activity, accumulating evidence demonstrates that statins also exhibit anti-inflammatory and anti-tumour activities. 23,24 Epidemiologic studies also showed the concomitant use of statins might be beneficial to cancer outcomes. 14,[20][21][22] In experimental animal models, statins are capable of suppressing angiogenesis, tumour invasion and metastasis.…”