The immunosuppressive drug mycophenolate mofetil impairs the adhesion capacity of gastrointestinal tumour cells

Abstract

Immunosuppression correlates with the development and recurrence of cancer. Mycophenolate mofetil (MMF) has been shown to reduce adhesion molecule expression and leucocyte recruitment into the donor organ. We have hypothesized that MMF might also prevent receptor-dependent tumour dissemination. Therefore, we have investigated the effects of MMF on tumour cell adhesion to human umbilical vein endothelial cells (HUVEC) and compared them with the effects on T cell-endothelial cell interactions. Influence of MMF on cellular adhesion to HUVEC was analysed using isolated CD4+ and CD8+ T cells, or WiDr colon adenocarcinoma cells as the model tumour. HUVEC receptors ICAM-1, VCAM-1, E-selectin and P-selectin were detected by flow cytometry, Western blot or Northern blot analysis. Binding activity of T cells or WiDr cells in the presence of MMF were measured using immobilized receptor globulin chimeras. MMF potently blocked both T cell and WiDr cell binding to endothelium by 80%. Surface expression of the endothelial cell receptors was reduced by MMF in a dose-dependent manner. E-selectin mRNA was concurrently reduced with a maximum effect at 1 microm. Interestingly, MMF acted differently on T cells and WiDr cells. Maximum efficacy of MMF was reached at 10 and 1 microm, respectively. Furthermore, MMF specifically suppressed T cell attachment to ICAM-1, VCAM-1 and P-selectin. In contrast, MMF prevented WiDr cell attachment to E-selectin. In conclusion, our data reveal distinct effects of MMF on both T cell adhesion and tumour cell adhesion to endothelial cells. This suggests that MMF not only interferes with the invasion of alloactivated T cells, but might also be of value in managing post-transplantation malignancy.

Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy

“…MMF might also act on further adhesion proteins which are relevant for tumor recurrence and dissemination. An in vitro study published recently refers to the sLeX-selectin pathway targeted by MMF [27]. CD44 glycoproteins as well as receptors of the cadherin family might also be modulated under MMF-based immunosuppressive regimen.…”

Efficiency of late conversion from mycophenolate mofetil to everolimus in kidney graft recipients with posttransplant malignancy

“…Данные о проонкогенном и антионкогенном эффекте производ-ных микофеноловой кислоты противоречивы как по клиническим данным, так и в исследованиях in vitro. Если в одних исследованиях in vitro их применение усиливало митогенные процессы и инвазивность опухолевых клеток [51,52], то в других, напротив, предотвращало опухолевую диссеминацию [53,54]. Кроме того, известно, что микофенолаты усиливают противогерпетическую активность ацикловира и ган-цикловира, потенциально снижая вероятность ПТЛЗ, индуцированных вирусом Эпштейна-Барр [55].…”

Downregulation of telomerase maintenance-related ACD expression in patients undergoing immunosuppresive therapy following kidney transplantation

“…Administration of MMF has been shown to result in a clear antitumor effect against leukemia and lymphoma (45,46) and against colon and prostate carcinoma cells (47). Additionally, MMF suppresses glycosylation and the expression of a number of adhesion molecules in solid tumor dissemination (47), while inhibiting the adhesion of colon adenocarcinoma cells to endothelial cells (39,48).…”