Negative Modulation of the Angiogenic Cascade Induced by Allosteric Kinesin Eg5 Inhibitors in a Gastric Adenocarcinoma In Vitro Model.

Alessia Ricci,Donatella Del Bufalo,Amelia Cataldi,Marialucia Gallorini,Ilaria D’Agostino,Susi Zara,Simone Carradori

doi:10.3390/molecules27030957

Alessia Ricci, Donatella Del Bufalo + Show 5 more

Open Access

https://doi.org/10.3390/molecules27030957

Copy DOI

Abstract

Eg5 is a kinesin essential in bipolar spindle formation, overexpressed in tumours, thus representing a new target in cancer therapy. We aimed at evaluating the anti-cancer activity of Eg5 thiadiazoline inhibitors 2 and 41 on gastric adenocarcinoma cells (AGS), focusing on the modulation of angiogenic signalling. Docking studies confirmed a similar interaction with Eg5 to that of the parent compound K858. Thiadiazolines were also tested in combination with Hesperidin (HSD). Cell cycle analysis reveals a reduction of G1 and S phase percentages when 41 is administered as well as HSD in combination with K858. Western blot reveals Eg5 inhibitors capability to reduce PI3K, p-AKT/Akt and p-Erk/Erk expressions; p-Akt/Akt ratio is even more decreased in HSD+2 sample than the p-Erk/Erk ratio in HSD+41 or K858. VEGF expression is reduced when HSD+2 and HSD+41 are administered with respect to compounds alone, after 72 h. ANGPT2 gene expression increases in cells treated with 41 and HSD+2 compared to K858. The wound-healing assay highlights a reduction in the cut in HSD+2 sample compared to 2 and HSD. Thus, Eg5 inhibitors appear to modulate angiogenic signalling by controlling VEGF activity even better if combined with HSD. Overall, Eg5 inhibitors can represent a promising starting point to develop innovative anti-cancer strategies.

Highlights

Gastric cancer is the fifth most frequent type of cancer and deadly disease diagnosed worldwide
To evaluate the possibility of the new Eg5 inhibitors to modulate the angiogenic molecular cascades, we studied the modulation of PI3K/Akt pathway and VEGF expression and secretion in the AGS cell line
The rise in interest in this protein is related to the discovery of novel drugs able to suppress its activity in tumours characterized by kinesin overexpression and, with this strategy, indirectly target the mitotic spindle, which is one of the most important goals of chemotherapy

Summary

Introduction

Gastric cancer is the fifth most frequent type of cancer and deadly disease diagnosed worldwide. It was responsible for 1,000,000 new cases of cancer Several causes can trigger gastric cancer development, among them, pathogenic infections such as Helicobacter pylori, which represents 90% of new gastric cancer cases, [3] and Epstein–Barr virus; non-pathogenic causes (familial and hereditary conditions, smoking, diet, alcohol, etc.), sedentary lifestyle, and others are included [4,5]. Considering that prevention is the most important approach, there is not a standard therapy to treat gastric cancer; complete surgical resection remains the best option to cure patients. The discovery of novel treatment options for gastric cancer to improve patient survival still represents a crucial point

Objectives

Methods

Results

Discussion

Conclusion