Tehran University Medical Journal

Background: Vascular endothelial growth factor (VEGF) has mitogenic effect for endothelial cells and is an important mediator of tumor expansion, metastasis and angiogenesis in vivo. Isosorbide dinitrate, as a nitric oxide donor, has been widely used in treatment of many cardiovascular diseases such as congestive heart failure and acute coronary syndromes. Furthermore this drug was found to have inhibitory effect on angiogenesis, tumor growth and metastasis in vivo. In the present study we evaluated the isosorbide effect on the VEGF production using some human leukemic cell lines.

Methods: Human leukemic MOLT-4, JURKAT and U937 cells were cultured in complete RPMI medium. The cells at the exponential growth phase were then incubated with different concentrations of Isosorbide (4´10^-7 -4´10^-4 M) in the presence or absence of PMA (25ng/ml) for 24 hours. The VEGF concentrations in the culture supernatants were measured by enzyme immunoassay kits (R&D systems) according to the manufacturer's instructions.

Results: The level of VEGF produced by the human leukemic cell lines which was treated with different concentrations of isosorbide, did not show any significant difference with untreated control cells.

Conclusions: The results of this study showed that isosorbide had no significant effect on VEGF production. Our findings suggest that anti-angiogenesis effect of isosorbide could be mediated through VEGF-independent mechanism(s). Further studies are warranted to determine definite isosorbide effect on VEGF and other angiogenic factors production in patients as well as animal models.

Background: Isosorbide dinitrate has been broadly used in the treatment of various ischemic heart diseases. Isosorbide is a nitric oxide donor which increases blood flow to tumors through vasodilatation and consequently accelerates the access of chemo-drugs to them. Furthermore, this drug has inhibitory effects on angiogenesis, tumor growth and metastasis in vivo. Moreover, its ant-inflammatory effects have also been reported. In the present study we evaluated the effects of isosorbide on the proliferative activity of fibrosarcoma WEHI-164 cell line and peripheral blood mononuclear cells (PBMCs).

Methods: WEHI-164 fibrosarcoma cells and human PBMCs were cultured in complete Roswell Park Memorial Institute (RPMI) 1640 medium with 10% fetal bovine serum and 2×104 cells/mL for WEHI-164 and 2×105 cells/mL for PBMCs. The cells were then incubated at the exponential growth phase with different concentrations of isosorbide (4×10-6-1.6×10-3 M) for 24, 48 and 72 hours. Subsequently, isosorbide effects on proliferation of the cells were evaluated by trypan blue dye exclusion (TB) test and MTT assay. Statistical comparisons between groups were made by analysis of variance.

Results: The proliferative activity of WEHI-164 fibrosarcoma cells and human PBMCs treated with different concentrations of isosorbide, did not show any significant difference with untreated control cells.

Conclusion: The results of this study showed that isosorbide neither had any significant effects on the proliferative activity of fibrosarcoma WEHI-164 cells nor on human PBMCs. Our findings suggest that anti-tumoral effects of isosorbide reported by other investigators may be mediated through non-cytotoxic mechanisms.