The natural product honokiol inhibits calcineurin inhibitor-induced and Ras-mediated tumor promoting pathways

• Calcineurin inhibitors (CNIs) are very good agents to prevent allograft rejection.
• However, they can induce tumor-promoting pathways through activation of ras.
• The natural product honokiol down-regulated CNI-induced and Ras-mediated pathways.
• It inhibited CNI-induced survival of renal cancer cells.
• Thus, honokiol treatment may prevent CNI-induced tumor growth in transplant patients.

Although calcineurin inhibitors (CNIs) are very useful in preventing allograft rejection, they can mediate a rapid progression of post-transplantation malignancies. The CNI cyclosporine A (CsA) can promote renal tumor growth through activation of the proto-oncogene ras and over-expression of the angiogenic cytokine VEGF; the ras activation also induces over-expression of the cytoprotective enzyme HO-1, which promotes survival of renal cancer cells. Here, we show that the natural product honokiol significantly inhibited CsA-induced and Ras-mediated survival of renal cancer cells through the down-regulations of VEGF and HO-1. Thus, honokiol treatment may help to prevent tumor-promoting effects of CsA in transplant patients.