Repurposing Antihelmintic Drugs for Pancreatic Cancer

Studies on repurposing FDA-approved anthelmintic drugs for pancreatic cancer remain scarce. In this study, we showed that Food and Drug Administration-approved benzimidazoles fenbendazole, mebendazole, oxibendazole, and parbendazole significantly reduced viability of AsPC-1 and Capan-2 pancreatic cancer cell lines.

Inhibiting the formation of microtubules, an essential protein scaffolding forming the cytoskeleton, they altered cell shape and migration, drastically influenced the DNA damage response and promoted apoptosis. Combinations of these drugs with gemcitabine synergistically reduced cell viability.
What is fenbendazole?

Fenbendazole (Panacur, Safe-Guard) is an anthelmintic medication used to treat and prevent intestinal parasites such as roundworms, hookworms, lungworms, whipworms, and some tapeworms. It is also employed off-label to protect against other parasites such as giardia in puppies.

The drug works by inhibiting the action of certain enzymes, thus preventing the breakdown and/or synthesis of the cytoskeletal proteins that form microtubules. Its broad spectrum activity makes it a potent medication with few side effects.

Penn researchers found that fenbendazole, when combined with gemcitabine, shrunk tumors and/or halted cancer growth in preclinical models of pancreatic cancer, including those with the difficult-to-treat KRAS mutation. This new finding may help improve survival rates for this deadly disease, which is usually diagnosed in the late stages when it has already spread to other organs. The study was published today in Cancer Discovery.
How does fenbendazole work?

Pancreatic cancer is hard to detect in its early stages, and by the time it is diagnosed, it’s often too late to save patients. That’s why researchers are working to develop better ways to treat this deadly disease, and a new study suggests an old anti-parasitic drug might be one way.

The team used genetically engineered mouse models and computational methods to map the earliest changes in pancreatic cells that lead to tumor initiation, progression and metastasis. They found that as pancreatic epithelial cells progressed toward a cancerous state, they become more plastic and expand their ability to communicate with other cells around them.

In the study, the researchers treated two types of pancreatic cancer cell lines—AsPC-1 and Capan-2, which both contain mutations in the KRAS gene. They then exposed the cells to fenbendazole, mebendazole and oxibendazole at different concentrations, or in combination with gemcitabine, for 72 hours. They observed that treatment with the drugs significantly decreased cell viability and proliferation, as well as induced apoptosis.

Scientists studied the effects of fenbendazole in combination with radiation and other drugs on cell cultures and mice tumors. They found that fenbendazole, a broad-spectrum antihelminthic drug, has cytotoxic and antitumor activity. When combined with radiation and the nitroheterocyclic chemotherapeutics docetaxel and gemcitabine, it produced additive toxicity in cell cultures and reduced tumor growth and survival in mouse models. These results suggest that fenbendazole may be effective as a pancreatic cancer treatment in combination with other therapies.

Fenbendazole kills parasitic worms by binding to their tubulin and disrupting the microtubule equilibrium (see figure below). The tubulin is both a skeleton for the cell and a highway for transport, so it’s vital to the organism’s function. But in the presence of fenbendazole, tubulin deforms and collapses, starving the parasite to death. In a study published in Scientific Reports, researchers showed that a similar mechanism may work for cancer cells. They found that fenbendazole and a related compound, mebendazole, can slow cancer cell proliferation in mice and in human cancer cells grown in the laboratory.
Side effects

Researchers have discovered that an antiparasitic drug can prevent the development of pancreatic cancer. The medication, mebendazole (Panacur C), works to inhibit the formation of microtubules in cells. This causes them to collapse from within, cutting off the cancer’s supply of nourishment. This is how it works:

In the cell, a protein called tubulin makes up microtubules that give the structure and shape to cells. While textbook depictions of cells often portray them as amorphous bags of liquid, they actually have a highly dynamic cytoskeleton made up of the protein scaffolding, or cytoskeleton.

Fenbendazole interferes with the creation of tubulin by binding to it and blocking its polymerization. This leads to the disruption of microtubule dynamics and a blockage in glucose uptake by inhibiting the expression of GLUT 4 in the cancer cells. This results in preferential elimination of cancer cells both in vitro and in vivo. This is a significant finding that could lead to new approaches for treating pancreatic cancer and other tumors, particularly those in patients with comorbidities and compromised immune systems.fenbendazole for pancreatic cancer

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