Fenbendazole (FBZ) exerts multi-targeted anticancer activity by simultaneously disrupting cytoskeletal structure, activating tumor suppressor pathways, blocking energy metabolism, and inducing selective oxidative stress across malignant cells.
1. Microtubule Disruption & G2/M Mitotic Blockade
Spindle Poisoning: FBZ acts as a moderate microtubule-destabilizing agent that binds tubulin at the colchicine-binding site, interfering with dynamic spindle formation.
Cell Cycle Arrest: Disrupting microtubule assembly triggers cell cycle arrest at G2/M, causing multinucleation and driving rapidly dividing cells into mitotic catastrophe.
G2/M Checkpoint Regulators: Mechanistically, FBZ enforces a G2/M blockade by upregulating cyclin B1, activating the CDK1–cyclin B1 complex, suppressing Wee1 expression, and promoting activating phosphorylation of cdc25C (Ser198).
2. p53 Stabilization & Mitochondrial Apoptosis
Proteasomal Inhibition: FBZ impairs proteasomal degradation, leading to accumulation and stabilization of the p53 tumor suppressor protein, along with downregulation of its negative regulators, Mdm2 and MdmX.
Mitochondrial Translocation: Active p53 translocates to the mitochondria, depolarizing the mitochondrial membrane potential and releasing cytochrome c into the cytosol.
Caspase Cascade: Cytochrome c release initiates intrinsic programmed cell death, upregulates pro-apoptotic Bax, and triggers the caspase-3/7/8/9 cleavage cascade and PARP cleavage.
3. Disruption of Energy Metabolism (Warburg Effect)
Glucose Deprivation: Cancer cells rely heavily on aerobic glycolysis for rapid growth and survival. FBZ directly blocks cellular glucose uptake by downregulating GLUT-1/4 transporters.
Hexokinase II Inhibition: FBZ inhibits Hexokinase II (HK II), the initial rate-limiting enzyme in glycolysis, reducing intracellular lactate and metabolically starving tumor cells.
4. Selective Redox Modulation & Ferroptosis
ROS Elevation: FBZ selectively drives a surge in intracellular reactive oxygen species (ROS)—specifically superoxide and hydroperoxides—in malignant cells, activating the pro-apoptotic MEK3/6-p38-MAPK pathway while sparing normal, non-transformed cells.
Bypassing Chemoresistance: In 5-fluorouracil (5-FU)-resistant tumor models, FBZ induces apoptosis independently of wild-type p53 while downregulating GPX4 and SLC7A11 to trigger iron-dependent lipid peroxidation (ferroptosis).
5. Dual-Targeting of Cancer Stem Cells & Metastasis
Targeting Stemness: Beyond bulk tumor cells, FBZ eliminates therapy-resistant cancer stem cells (CSCs) by suppressing key stemness markers, including CD133, CD44, OCT4, SOX2, and ALDH1.
Invasion Blockade: FBZ downregulates matrix metalloproteinases (MMP-2 and MMP-9), effectively inhibiting cell migration, tissue invasion, and metastatic colonization.
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