Cyclodextrin Dispersion of Mebendazole and Flubendazole Improves In Vitro Antiproliferative Activity

Daliana Minda,Codruța Soica,Cristina Trandafirescu,Adrian Voicu,Stefana Avram,Roxana Racoviceanu,Andrei Motoc,Ioana Macasoi,Alexandra Mioc,Marius Mioc,Christian Banciu

doi:10.3390/pr9122185

Daliana Minda, Codruța Soica + Show 9 more

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https://doi.org/10.3390/pr9122185

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Abstract

Mebendazole and flubendazole are antihelmintic drugs that have re-entered the research spotlight due to their exhibited anticancer effects, thus making them strong candidates as repurposed drugs. However, these benzimidazole derivatives exhibit poor solubility in water and various organic solvents, which limits their bioavailability. With the aim of obtaining an improved drug solubility and increased biological effect, mebendazole and flubendazole were complexed with 2-hydroxypropyl-β-cyclodextrin (HPBCD). The binary 1:1 conjugates were physicochemically evaluated by X-ray diffraction, thermal analysis, and FTIR spectroscopy, revealing the formation of physical mixtures. The increased aqueous solubility of the binary 1:1 conjugates vs. pure benzimidazole compounds was demonstrated by performing dissolution tests. The in vitro antiproliferative activity of mebendazole and flubendazole, as well as their combination with HPBCD, was tested on two cancer cell lines, human melanoma—A375 and pulmonary adenocarcinoma—A549 by the MTT assay. The cytotoxic activity manifested in a dose-dependent manner while the presence of HPBCD increased the antiproliferative activity against the targeted cells. Treatment of A375 and A549 cell lines with the binary conjugates induced a significant inhibition of mitochondrial respiration, as revealed by high-resolution respirometry studies. Molecular docking analysis showed that one of the mechanisms related to MEB and FLU cytotoxic activity may be due to the inhibition of MEK/ERK proteins.

Highlights

Mebendazole (methyl (5-benzoyl-1H-benzimidazol-2-yl) carbamate) (MEB) and flubendazole (methyl N-[6-(4-fluorobenzoyl)-1H-benzimidazol-2-yl] carbamate) (FLU) (Figure 1)are typical benzimidazole compounds used as broad-spectrum antihelmintic drugs for over 40 years, in both veterinary and human medicine [1]
The binary conjugates were prepared by kneading each drug with a β-cyclodextrin derivative with high water solubility, hydroxypropyl-β-cyclodextrin (HPBCD)
The current study study aimed aimedtotoassess assess influence a hydrophilic cyclodextrin, The current thethe influence of aofhydrophilic cyclodextrin, HPBCD, upon thethe cytotoxic activity ofoftwo

Summary

Introduction

Are typical benzimidazole compounds used as broad-spectrum antihelmintic drugs for over 40 years, in both veterinary and human medicine [1]. MEB is designated an essential intestinal antihelminthic by WHO. They bind to β-tubulin and act as a tubulin polymerase inhibitor [2]. Mainly used against gastrointestinal parasitic infections in animals, FLU may be administered parenterally with high macrofilaricidal efficacy in humans [1]. Both drugs have re-entered the attention of researchers with the drug repurposing initiative, revealing strong anticancer effects through various molecular mechanisms. MEB exhibits several characteristics that make it a candidate as a repurposed drug, such as low toxicity and price, suitable pharmacokinetic profile, and facile administration [3]

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