Fenben for Colorectal Cancer
Fenben, an anthelmintic drug that is active against parasitic worms, exhibits anti-neoplastic activity and has been recently repurposed to overcome multidrug resistance in 5-fluorouracil-resistant colorectal cancer cells. We report that fenbendazole (FZ) induces multiple pathways leading to cell death in cancer cells, including mitotic arrest and pyroptosis, and causes mitochondrial injury with caspase-3-poly(ADP-ribose) polymerase activation. Furthermore, FZ inhibits glycolysis by blocking the expression of GLUT transporters and hexokinase II, a key enzyme in glucose metabolism.
To investigate the mechanisms of action of fenbendazole, we performed cell proliferation assays and flow cytometry. We found that fenbendazole induces time-dependent anti-proliferative effects in both wild-type and 5-fluorouracil resistant SNU-C5/5-FUR colorectal cancer cells. In addition, fenbendazole significantly enhanced the effect of microtubule targeting drugs taxol and 2 deoxyglucose (2DG) on cell viability and cell cycle progression. Moreover, FZ demonstrated synergistic effects in combination with dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, to shift the energy source of cells from glycolysis to oxidative phosphorylation.
To further evaluate the synergistic effect of fenbendazole and RAPA, we prepared various FEN:RAPA molar ratios in mPEG-b-PCL micelles. The mPEG-b-PCL particles were selected due to their consistent size and high encapsulation efficiency (EE) and drug loading capacity (DL). In vitro cellular toxicity assays showed that the mixture of free FEN and RAPA had less potent cytotoxic activity than the pure FEN or RAPA solutions alone, and the combination of FEN with RAPA resulted in the strongest synergistic effect against A549 cells. fenben for cancer