Flubendazole is an anthelmintic. Its brand name is Flutelmium, which is a paste manufactured by Janssen Pharmaceutica NV used by veterinarians for protection against internal parasites and worms in dogs and cats. Other brands are Flubenol, Biovermin and Flumoxal. It is also available for human use to treat worm infections. It is available over the counter (OTC) in Europe.

Flubendazol – Historia

Since 2000, Flubendazole-treated sand has increasingly been designed at a landscape scale in many UK grouse hunting moors in an attempt to reduce the impact on bird numbers of the worm. Evidence of high worm load is required before a veterinarian can dispense and sell the product, known as “medicated litter.”

However, there has been growing concern about pollutants entering groundwater escaping from moorlands, as well as their use in agricultural settings and their presence in manure. Researchers are beginning to gather research evidence to inform policy development on the presence of this and other veterinary medicines in a broader setting.

Flubendazol – Usos

Flubendazole was shown to exert anti-leukemia and anti-myeloma activity through inhibition of microtubule function. Here, flubendazole was evaluated for its effects on the viability of a total of 461 cancer cell lines. Neuroblastoma was identified as a highly flubendazole-sensitive cancer entity in a screen of 321 cell lines from 26 cancer entities.

Flubendazole also reduced the viability of five primary neuroblastoma samples at nanomolar concentrations believed to be achievable in humans and inhibited vessel formation and neuroblastoma tumor growth in the chicken chorioallantoic membrane assay. The acquisition of resistance is a major problem in high-risk neuroblastoma. 119 cell lines from a panel of 140 neuroblastoma cell lines with acquired resistance to various anticancer drugs were sensitive to flubendazole at nanomolar concentrations.

Tubulin binding resistant cell lines showed the highest flubendazole IC50 and IC90 values, but the differences between drug classes did not reach statistical significance. Flubendazole induced p53-mediated apoptosis. SiRNA-mediated reduction of the p53 p21, BAX, or PUMA targets reduced the sensitivity of neuroblastoma cells to PUMA-depleted flubendazole, resulting in the most pronounced effects.

The MDM2 inhibitor and the p53 activator nutlin-3 increased the efficacy of flubendazole while RNAi-mediated p53 depletion reduced its activity. In conclusion, flubendazole represents a possible treatment option for neuroblastoma, including cells refractory to therapy.

Anthelmintic benzimidazoles, including mebendazole and flubendazole, have been shown to exert anticancer activity by mechanisms including inhibition of microtubule function1,2,3,4,5,6,7.

Mebendazole affects the viability of cancer cells in experimental systems of a wide spectrum of cancerous entities, including lung cancer, breast cancer, ovarian cancer, adrenocortical carcinoma, osteosarcoma, melanoma, glioblastoma and colorectal carcinoma1,3,4,5 , 6.7. More recently, flubendazole has been shown to affect the viability of leukemia and myeloma cells at nanomolar concentrations2.

Here, flubendazole was screened on a panel of 321 cell lines, including cell lines from 26 cancer entities. Between leukemia and multiple myeloma, neuroblastoma was identified as a cancerous entity highly sensitive to flubendazole.

Flubendazole showed broad activity in primary neuroblastoma cells and a panel of 140 neuroblastoma cell lines with acquired drug resistance. The anti-neuroblastoma activity of flubendazole involved p53-mediated apoptosis and the MDM2 inhibitor and p53 activator nutlin-3 strongly potentiated the effects of flubendazole. A water-soluble flubendazole- (2-hydroxypropyl) -β-cyclodextrin preparation inhibited vessel formation and tumor growth in the chicken chorioallantoic membrane (CAM) model.

Flubendazole – Results

Flubendazole was examined in a panel of 321 cancer cell lines from 26 cancer entities. Concentrations of 1 μM appear pharmacologically achievable based on previous studies in mice that demonstrated a dose of 5 mg / kg to produce a Cmax of 3.6 μM8. The maximum concentration tested was 5 µM. Multiple myeloma, neuroblastoma, and leukemia / lymphoma consistently belonged to the cancerous entities that showed the highest sensitivity to flubendazole.

This confirmed previous research that had suggested that multiple myeloma and leukemia were cancers sensitive to flubendazole2 and identified neuroblastoma as an additional entity sensitive to flubendazole. Statistical tests using the Wilcoxon rank sum test with subsequent Benjamini-Hochberg correction indicated that flubendazole IC90 values ​​in neuroblastoma cells were significantly lower than those of 21 of the other 25 cancer cell types investigated.

Effects of flubendazole on primary neuroblastoma cells

Primary neuroblastoma cells isolated from the bone marrow of five patients with metastases from INSS stage 4 disease showed similar sensitivity to flubendazole, as did the neuroblastoma cell lines investigated. IC90 values ​​ranged from 464.7 to 612.2 nM.

Flubendazole concentrations that decreased cancer cell viability by 90% (IC90) and 50% (IC50) were determined by the MTT assay after 5 days of incubation. Values ​​are expressed as mean ± standard deviation.

Cancer cell sensitivity to flubendazole

The anticancer effects of many anticancer drugs are affected by the expression of ATP-binding cassette transporters (ABC), including ABCB1 and ABCG214,15. UKF-NB-3 cells were transduced with lentiviral vectors encoding ABCB1 or ABCG2, respectively, as previously described 16,17.

Expression of ABCB1 increased the resistance of UKF-NB-3 cells to the vincristine substrate ABCB1 but not to flubendazole. The ABCB1 inhibitor, verapamil, sensitized neuroblastoma cells expressing ABCB1 to vincristine, but not to flubendazole. Similarly, the expression of ABCG2 increased the resistance of UKF-NB-3 cells to the substrate mitoxantrone ABCG2 but not to flubendazole. The ABCG2 inhibitor WK-X-3418 primed UKF-NB-3 cells expressing ABCG2 to mitoxantrone but not to flubendazole.

Cell death induced by many anticancer drugs involves activation of p5319. Flubendazole induced the expression of the target genes p53 CDKN1A (encoding p21), BAX and BBC3 (encoding PUMA) and signs of apoptosis (activation of caspase 3, cleavage of PARP) in UKF-NB-3 cells.

The flubendazole-treated p53-depleted UKF-NB-3 cells (UKF-NB-3p53shRNA) showed a lack of expression of the flubendazole-induced p53 target gene, and reduced flubendazole-induced caspase 3 activation and PARP cleavage. Furthermore, flubendazole induced a stronger increase in the sub-G1 fraction in wild-type p53 expression than in p53-depleted cells. Different downstream p53 molecules appear to be involved in the effects induced by flubendazole.

SiRNA-mediated depletion of Bax, p21 and PUMA impaired flubendazole sensitivity of PUMA-depleted UKF-NB-3 cells, causing the strongest effects. Furthermore, siRNA-mediated depletion of Bax, p21, and PUMA inhibited flubendazole-induced caspase 3/7 activation.

Samantha Robson
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Dr. Samantha Robson ( CRN: 0510146-5) is a nutritionist and website content reviewer related to her area of ​​expertise. With a postgraduate degree in Nutrition from The University of Arizona, she is a specialist in Sports Nutrition from Oxford University and is also a member of the International Society of Sports Nutrition.

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