Bevacizumab Versus Anti-preeclamptic Drugs: Evaluation With Three-dimensionally Co-cultured Human Mini Tumors.

Abstract

Both bevacizumab (BEV) and soluble fms-like tyrosine kinase-1 (sFlt-1) have demonstrated anti-angiogenic effects, thereby causing hypertension and proteinuria. We hypothesized that anti-preeclamptic drugs that combat the action of sFlt-1 may reduce BEV's anti-tumor efficacy. 3D co-cultured human mini-tumors consisting of endothelial cells, fibroblasts, and cancer cells were developed. The influence of anti-preeclamptic drugs and BEV on the invasion of mini-tumors embedded in collagen gel was evaluated. Mini-tumor spheroids that contained MDA-MB-231 cells showed higher invasion ability than spheroids with A549. Among the six anti-preeclamptic drugs investigated, only nicorandil enhanced the invasion of mini-tumors and inhibited the action of BEV. Glibenclamide, an ATP-sensitive potassium channel inhibitor, completely quenched the action of nicorandil on mini-tumors. In the human mini-tumor model, nicorandil aggravated the invasion of mini-tumors. These data raise the possibility that concomitant use of nicorandil counteracts the efficacy of BEV therapy.