By How Many Different Mechanisms Does Fenbendazole Fight Cancer?

Executive Summary

• Fenbendazole has multiple impressive ways it fights against cancer in prevention and treatment.

Introduction

But to understand the impact of Fenbendazole on cancer, it is essential to know how many different ways Fenbendazole has this impact.

The most common Benzimidazoles are Fenbendazole, Mebendazole and Albendazole. In our analysis, we include research for all three drugs together in articles as they are very similar to one another and it improves the ability to tie together different studies. You may see the following terms/acronyms used.

• FZ or FBZ means Fenbendazole
• MBZ means Mebendazole
• AZ means Albendazole

The Mechanisms Whereby Fenbendazole Addresses Cancer?

These include the following items but are not limited to the following items.

Mechanism #1: Attacking the Mitochondria in Cancer Cells

Mitochondria are the energy-producing “mini cells” (technically called organelles) within the overall cells of the body. FZ has an affinity for undermining the mitochondria within cancer cells while leaving the body’s healthy cells alone.

FZ undermines the overall mitochondrial function in cancer cells and undermines glucose uptake and metabolism in cancer cells.

This quote is from the article Anti-cancer effects of fenbendazole on 5 − fluorouracil-resistant colorectal cancer cells.

The anticancer activity of FZ has been investigated in different cell lines.

FZ exhibits depolymerizing MT activity toward human cancer cell lines that manifests as a significant anticancer effect in vitro and in vivo.

The mechanism of action of the FZ antitumor effect is predominantly the disruption of MT dynamics, p53 activation, and the regulation of genes associated with multiple biological pathways. FZ treatment also causes the depletion of glucose uptake in cancer cells by downregulating key glycolytic enzymes and GLUT transporters [242,733]. FZ selectively inhibits the growth of H4IIE cells by upregulating p21, and downregulating cyclins B and D at G1 / S and G2 / M phases, resulting in apoptosis exclusively in actively growing cells with low confluency, but not in quiescent cells.

FZ treatment in human cancer cells induced decreased mitochondrial membrane potential, ROS production, ER stress, and cytochrome c release, eventually leading to cancer cell death [34]. FZ exhibits considerable affinity for mammalian tubulin in MT and is toxic in human cancer cells (H460, A549) at micromolar concentrations.

Additionally, FZ exposure causes the mitochondrial translocation of p53, and effectively inhibits the expression of GLUT transporters, glucose uptake, and levels of hexokinase, which is a key glycolytic enzyme potentially linked to p53 activation and the alteration of MT dynamics. Orally administered FZ successfully blocked the growth of human xenografts in a nu / nu mice model [27]. Moreover, Qiwen et al. reported that FZ treatment is toxic to EMT6 mouse mammary tumor cells in vitro, with toxicity increasing after 24 h incubation with high FZ doses. However, FZ did not alter the dose–response curves for radiation on EMT6 cells under either aerobic or hypoxic conditions [24]. In contrast, Ping et al. reported that FZ or vitamins alone had no growth inhibitory effect on P493-6 human lymphoma cell lines in SCID mice. In combination with vitamin supplements, FZ significantly inhibited tumor growth through its antimicrotubular activity [28]. The effect of a therapeutic diet containing 150 ppm FZ for 6 weeks on the growth of EMT6 mouse mammary tumors in BALB / c mice injected intradermally was examined. The results revealed that the FZ diet did not alter tumor growth, metastasis, or invasion. Therefore, the authors suggested being cautious in applying FZ diets to mouse colonies used in cancer research. [29]. HL-60 cells, a human leukemia cell line, were treated with FZ to investigate the anticancer potential in the absence or presence of N-acetyl cysteine (NAC), an inhibitor of ROS production. NAC could significantly recover the decreased metabolic activity of HL-60 cells induced by 0.5 – 1 μM FZ treatments. The results proved that FZ manifests anticancer activity in HL-60 cells via ROS production [35]. Ji-Yun also reported the antitumor effect of FZ and paclitaxel via ROS on HL-60 cells at a certain concentration [36]. Moreover, FZ and its synthetic analog induced oxidative stress by accumulating ROS.

How FZ Undermines the Cellular Glucose Metabolism of Cancer Cells

This quote is from the article Fenbendazole Suppresses Growth and Induces Apoptosis of Actively Growing H4IIE Hepatocellular Carcinoma Cells via p21-Mediated Cell-Cycle Arrest.

And this quote explains more on the interferenced with cancer cell glucose metabolism.
In general, metabolic alterations such as enhanced glucose uptake and glycolytic activity are observed in cancer cells.19) Although a number of studies seek to develop potential anticancer remedies targeting the dysregulated glucose metabolism in cancer cells, a successful attempt has yet to be reported. A recent study found that FZ effectively interferes with multiple steps in glucose metabolism including glucose uptake, expression of glucose transporters (GLUTs) and hexokinase in human non-small cell lung carcinoma (NSCLC) cells.20)

This quote is from the article Flubendazole induces mitochondrial dysfunction and DRP1-mediated mitophagy by targeting EVA1A in breast cancer.

Numerous studies have shown that the alteration of mitochondrial function affects tumorigenesis, progression, and resistance to therapy, including the biogenesis and turnover of mitochondria, fission and fusion dynamics, cell death regulation, oxidative stress regulation, metabolism and bioenergetics [9, 10].

Our data first suggested that flubendazole impairs mitochondrial outer membrane permeability and mitochondrial function, accompanied by mitophagy.

Mitiphogy is the process of removing damaged mitochondria. FBZ increases mitophagy in cancer cells at a very high rate.

The resultant excessive mitophagy contributed to mitochondrial damage and dysfunction induced by flubendazole, thus inhibiting breast cancer cells proliferation and migration.

In line with autophagy, mitophagy plays a double-faceted role in tumorigenesis in response to various stress conditions [44, 45]. Generally, mitophagy degrades the damaged mitochondria and prompts tumor cells to rapidly adapt to these hostile conditions, thereby supporting cell proliferation and evading activation of cell death programs [46]. However, excessive mitophagy impairs the stability of the mitochondrial microenvironment and contributes to tumor cells death [14].

In summary, our results suggest that DRP1-mediated mitophagy induced by EVA1A overexpression may be the primary contributing factor for mitochondrial damage and dysfunction in breast cancer cells in response to flubendazole treatment, resulting in inhibition of cell proliferation and migration.

Mechanism #2: Promoting Apoptosis in Cancer Cells

• A specific apoptosis mechanism – p53 activation — is a mechanism of apoptosis promotion.
• A Specific apoptosis mechanism – G2/M cell cycle arrest and apoptosis.

These quotes illustrate this.