Cancer stages describe the progression of a disease and can offer information about a person’s outlook. Stage 4 cancer has spread beyond its original location and may have affected other parts of the body. Treatment options are limited at this stage but can improve survival and quality of life. A popular cancer protocol called the Joe Tippens Fenbendazole Cancer Protocol consists of taking 222mg of fenbendazole (Panacur C) daily, seven days a week. The protocol has gained popularity following a video by an unlicensed veterinarian who claims that dog deworming medicine cured his small-cell lung cancer. Apoptosis Fenbendazole is a broad-spectrum benzimidazole anthelmintic that is used to treat parasites (pinworms, whipworms, roundworms, hookworms, and tapeworms) in animals. It is also used by some humans as part of a cancer treatment protocol called the Joe Tippens Protocol. It is sold as a dog dewormer under the brand names Panacur and Safe-Guard. It has a polymerization inhibitory effect on tubulin, the polymer that makes up microtubules. These structures provide structure and support for cells. Apoptosis is a form of cell death that can occur when these structures break down. It involves a series of morphological changes, including plasma membrane blebbing and separation of organelles into apoptotic bodies. Apoptotic bodies are phagocytosed by macrophages or other cells and degraded within lysosomes. Apoptosis is triggered by a combination of factors, such as mitochondrial injury and caspase-3-poly (ADP-ribose) polymerase activity. In addition, apoptosis is enhanced by ferroptosis, which involves lipid peroxidation and inactivation of the antioxidant enzyme glutathione peroxidase 4. In this case, the increase in free iron is caused by inhibition of cysteine uptake by SLC7A11. It triggers GPX4-mediated ferroptosis to release pro-apoptotic factors. Mitochondrial Injury The anthelmintic drug fenbendazole (FZ) belongs to the class of bendimidazole antiparasitics and has recently gained interest as a cancer treatment. However, to date no peer-reviewed study has confirmed that this medication can cure cancer in humans. FZ acts as a tubulin polymerization inhibitor, which prevents the assembly of microtubules that give cell shape and support structures [1]. This property is similar to that of cytotoxic anticancer drugs that target the formation of these structures and inhibit their growth (e.g. vinca alkaloids). Besides blocking tubulin polymerization, fenbendazole induces apoptosis and G2/M arrest through p53-p21 pathways in colorectal cancer cells. It also enhances apoptosis and ferroptosis-augmented apoptosis in 5-FU resistant cells. These processes are mainly dependent on mitochondria and involve oxidative stress, disruption of mitochondrial cristae, autophagy and necroptosis. However, it is unclear whether these processes are triggered directly by FZ or by an indirect mechanism. This is important, as a direct effect of FZ on mitochondria could lead to neurotoxicity and psychiatric disorders. Cell Cycle Arrest Fenbendazole inhibits tubulin polymerization, blocking cell-cycle progression. This causes mitosis to stop in G2. This allows the DNA to be repaired by other mechanisms, such as cell senescence or apoptosis. When fenbendazole was administered to a patient with stage 4 lung cancer, she experienced tumor shrinkage. While anthelmintics have long been used to treat parasites in animals, researchers are exploring the possibility that they could also cure human cancers. Using a flow cytometer, the authors determined that fenbendazole caused a G2/M arrest in 5-FU-sensitive SNU-C5 and p53 mutant SNU-C5/5-FUR CRC cells. The authors also determined that fenbendazole increased the expression of p53, p21 and p27Kip1 in the two cell types. It also stimulated autophagy and ferroptosis in SNU-C5 cells. Western blots revealed that fenbendazole induced Beclin-1-dependent autophagy in both cell lines. It also stimulated caspase-3, poly (ADP-ribose) polymerase (PARP), and cytochrome-C in both cell lines. Moreover, fenbendazole suppressed the RAS-related pathway in KRAS-mutant lung adenocarcinoma cells. Necroptosis Necroptosis is a form of programmed cell death that occurs through inflammation and mitochondrial dysfunction. Unlike apoptosis, necroptosis does not involve DNA fragmentation. The necroptosis process is triggered by extracellular signals and involves a specialized protein complex called the necrosome that consists of RIPK3 and MLKL. Phosphorylation of RIPK3 and MLKL is induced by the activation of death receptors and leads to their oligomerization, formation of the necrosome, and cell death. It has been reported that fenbendazole induces necroptosis in cancer cells with a KRAS mutation, but it does not promote autophagy or ferroptosis. It is important to understand the role of necroptosis in fenbendazole’s antitumor effects, as this may help guide clinical strategies to target the underlying molecular mechanisms.fenbendazole stage 4 cancer