Research has found that animal anthelmintic drugs known as benzimidazoles can be repurposed to treat cancer. Mebendazole, for example, has been shown to starve cancer cells by collapsing their tubulin structures and cutting off their supply of nutrients.
The viability of wild-type and 5-fluorouracil-resistant SNU-C5 colorectal cancer cells was evaluated after treatment with fenbendazole. A number of cell death pathways were investigated using flow cytometry.
Apoptosis
Apoptosis is a form of programmed cell death that occurs in multicellular organisms and some eukaryotic microorganisms. Apoptosis is characterized by a series of biochemical events that cause the cell to undergo characteristic changes and die. Apoptosis is distinct from necrosis, a process that involves uncontrolled cell proliferation and tissue damage.
During apoptosis, the plasma membrane becomes blebbing and loses its tight organization. The nucleus shrinks and the organelles are loosely packed, but still intact (Figure 2A). The cell will eventually fragment into apoptotic bodies containing tightly packed cytoplasmic organelles with or without nuclear fragments. The apoptotic bodies are then phagocytosed by macrophages, parenchymal cells, or other neoplastic cells and degraded in a specialized lysosome.
Riggins’s team is exploring whether mebendazole, an antiparasitic medication that kills parasitic worms by cutting off their supply of nutrition, could be used to treat pancreatic cancer. The drug works by inhibiting the formation of a protein called tubulin, which forms both the cell’s micro-skeleton and highway for transport.
Autophagy
Autophagy is a key maintenance tactic that allows cells to recycle cellular components and repurpose them as a source of energy. It is involved in a wide range of functions including eliminating misfolded or aggregated proteins, clearing damaged organelles such as mitochondria and endoplasmic reticulum, and eliminating intracellular pathogens. It is also important for balancing sources of energy during starvation. Researchers are currently working to understand how this housekeeping function is regulated, and it has been linked to aging and several diseases.
When a cell component is broken, autophagy is like the city workers who pick up your Amazon boxes: it signals that the recycling needs to be collected by recruiting small pieces of membrane to form a half circle – an autophagosome – around the defective part. This autophagosome then fuses with a compartment inside the cell called a lysosome, where enzymes work to reduce the malfunctioning parts to amino acids, which can either be removed from the cell, recycled as fuel, or used to make new proteins.
Ferroptosis
Recently, a new mode of programmed cell death has been described. It is called ferroptosis, and it is characterized by the accumulation of lipid reactive oxygen species (ROS). This non-apoptotic form of cell death has become the focus of intense research. It has also been associated with several diseases, including age-related macular degeneration, psoriasis and hemolytic disorders.
Ferroptosis is a complex biological process that can be induced by multiple mechanisms. It is a nexus of redox biology and lipid peroxidation metabolism, and it is regulated by a number of genes. It is also involved in the progression of certain diseases, such as acute myeloid leukemia and ischemic disorders.
The mechanism of ferroptosis is unclear, but it may involve mitochondrial dysfunction and lipid regulation. A variety of compounds have been shown to induce ferroptosis, and some are effective in preventing the formation of H2DCFDA-sensitive ROS. Trolox, DFO and U0126 prevented the formation of ROS in erastin-treated HT-1080 cells, indicating that these agents inhibit the activation of the core apoptotic machinery mediated by Bax and Bak.
Necroptosis
While apoptosis is considered the “default” cell death modality, necroptosis can also play an important role in tumor progression. Specifically, necroptosis is thought to be a fail-safe mechanism that protects against oncogenesis when key apoptotic mechanisms are impaired.
In contrast to apoptosis, necroptosis is characterized by the rupture of the plasma membrane and a highly inflammatory response. These features make necroptosis a powerful immunogenic cell death mode that can overcome apoptosis resistance.
The anthelmintic drug mebendazole, an anti-parasitic agent that is used to treat a wide range of animal parasites, such as roundworms, hookworms and whipworms in sheep, goats, cattle and horses, has recently been shown to kill cancer cells by collapsing their tubulin structure. The researchers found that mebendazole also promotes apoptosis in colorectal cancer cells by enhancing p53-dependent and p53-independent apoptotic cell death pathways. fenbendazole stage 4 cancer