In Silico and In Vitro Studies for Benzimidazole Anthelmintics Repurposing as VEGFR-2 Antagonists: Novel Mebendazole-Loaded Mixed Micelles with Enhanced Dissolution and Anticancer Activity

Ayman Abo Elmaaty; Khaled M Darwish; Amani Chrouda; Amira A Boseila; Mohamed A Tantawy; Sameh S Elhady; Afzal B Shaik; Muhamad Mustafa; Ahmed A Al-Karmalawy

doi:10.1021/acsomega.1c05519

In Silico and In Vitro Studies for Benzimidazole Anthelmintics Repurposing as VEGFR-2 Antagonists: Novel Mebendazole-Loaded Mixed Micelles with Enhanced Dissolution and Anticancer Activity

ACS Omega. 2021 Dec 22;7(1):875-899. doi: 10.1021/acsomega.1c05519. eCollection 2022 Jan 11.

Authors

Ayman Abo Elmaaty¹, Khaled M Darwish², Amani Chrouda^{3

4}, Amira A Boseila⁵, Mohamed A Tantawy^{6

7}, Sameh S Elhady⁸, Afzal B Shaik⁹, Muhamad Mustafa¹⁰, Ahmed A Al-Karmalawy¹¹

Affiliations

¹ Department of Medicinal Chemistry, Faculty of Pharmacy, Port Said University, Port Said 42526, Egypt.
² Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
³ Department of Chemistry, College of Science Al-Zulfi, Majmaah University, Al-Majmaah 11952, Saudi Arabia.
⁴ Laboratory of Interfaces and Advanced Materials, Faculty of Sciences, Monastir University, Monastir 5000, Tunisia.
⁵ Pharmaceutics Department, Egyptian Drug Authority EDA (Formerly Known as National Organization for Drug Control and Research NODCAR) Dokki, Giza 12611, Egypt.
⁶ Hormones Department, Medical Research Division, National Research Centre, Dokki, Giza 12622, Egypt.
⁷ Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo 12622, Egypt.
⁸ Department of Natural Products, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
⁹ Department of Pharmaceutical Chemistry, Vignan Pharmacy College, Jawaharlal Nehru Technological University, Vadlamudi 522 213, Andhra Pradesh, India.
¹⁰ Department of Medicinal Chemistry, Deraya University, Minia 61111, Egypt.
¹¹ Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt.

Abstract

Cancer is a leading cause of death worldwide and its incidence is unfortunately anticipated to rise in the next years. On the other hand, vascular endothelial growth factor receptor 2 (VEGFR-2) is highly expressed in tumor-associated endothelial cells, where it affects tumor-promoting angiogenesis. Therefore, VEGFR-2 is considered one of the most promising therapeutic targets for cancer treatment. Furthermore, some FDA-approved benzimidazole anthelmintics have already shown potential anticancer activities. Therefore, repurposing them against VEGFR-2 can provide a rapid and effective alternative that can be implicated safely for cancer treatment. Hence, 13 benzimidazole anthelmintic drugs were subjected to molecular docking against the VEGFR-2 receptor. Among the tested compounds, fenbendazole (FBZ, 1), mebendazole (MBZ, 2), and albendazole (ABZ, 3) were proposed as potential VEGFR-2 antagonists. Furthermore, molecular dynamics simulations were carried out at 200 ns, giving more information on their thermodynamic and dynamic properties. Besides, the anticancer activity of the aforementioned drugs was tested in vitro against three different cancer cell lines, including liver cancer (HUH7), lung cancer (A549), and breast cancer (MCF7) cell lines. The results depicted potential cytotoxic activity especially against both HUH7 and A549 cell lines. Furthermore, to improve the aqueous solubility of MBZ, it was formulated in the form of mixed micelles (MMs) which showed an enhanced drug release with better promising cytotoxicity results compared to the crude MBZ. Finally, an in vitro quantification for VEGFR-2 concentration in treated HUH7 cells has been conducted based on the enzyme-linked immunosorbent assay. The results disclosed that FBZ, MBZ, and ABZ significantly (p < 0.001) reduced the concentration of VEGFR-2, while the lowest inhibition was achieved in MBZ-loaded MMs, which was even much better than the reference drug sorafenib. Collectively, the investigated benzimidazole anthelmintics could be encountered as lead compounds for further structural modifications and thus better anticancer activity, and that was accomplished through studying their structure-activity relationships.