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Fulltext Cyclodextrin inclusion complex inhibits circulating galectin-3 and FGF-7 and affects the reproductive integrity and mobility of Caco-2 cells

Maki MAA, Cheah SC, Bayazeid O, Kumar PV

Sci Rep, 2020 10 15;10(1):17468.
PMID: 33060727 DOI: 10.1038/s41598-020-74467-1

Galectin-3 (Gal-3) is a carbohydrate-binding protein, that promotes angiogenesis through mediating angiogenic growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). There is strong evidence confirming FGF involvement in tumor growth and progression by disrupting cell proliferation and angiogenesis. In this study, we investigated the effect of β-cyclodextrin:everolimus:FGF-7 inclusion complex (Complex) on Caco-2 cell migration, cell motility and colony formation. In addition, we examined the inhibitory effect of the Complex on the circulating proteins; Gal-3 and FGF-7. Swiss Target Prediction concluded that Gal-3 and FGF are possible targets for β-CD. Results of the chemotaxis cell migration assay on Caco-2 cell line revealed that the Complex has higher reduction in cell migration (78.3%) compared to everolimus (EV) alone (58.4%) which is possibly due to the synergistic effect of these molecules when used as a combined treatment. Moreover, the Complex significantly decreased the cell motility in cell scratch assay, less than 10% recovery compared to the control which has ~ 45% recovery. The Complex inhibited colony formation by ~ 75% compared to the control. Moreover, the Complex has the ability to inhibit Gal-3 with minimum inhibitory concentration of 33.46 and 41 for β-CD and EV, respectively. Additionally, β-CD and β-CD:EV were able to bind to FGF-7 and decreased the level of FGF-7 more than 80% in cell supernatant. This confirms Swiss Target Prediction result that predicted β-CD could target FGF. These findings advance the understanding of the biological effects of the Complex which reduced cell migration, cell motility and colony formation and it is possibly due to inhibiting circulating proteins such as; Gal-3 and FGF-7.
In silico-based Approach to Investigate the Ability of PEGylated Rapamycin to Inhibit Galectin-3

Abdelkarim Maki MA, Kumar PV, Elumalai M, Bayazeid O

Curr Drug Discov Technol, 2021;18(3):451-456.
PMID: 31969105 DOI: 10.2174/1570163817666200122162042

AIMS: To utilize in silico-based approach for investigating the ability of PEGylated rapamycin as a competitive inhibitor to Galectin-3 for curing various diseases or that may provide an attractive strategy for treatment of a wide variety of tumors.
BACKGROUND: Galectin-3 (Gal-3) signaling protein is a unique member of lectin family present at the cell surface, intracellularly in both the nucleus and cytoplasm and extracellularly in the general circulation. Circulating Gal-3 is present in both normal and cancer cells. High levels of circulating Gal-3 have been proven to be associated with inflammation and fibrosis in several acute and chronic conditions, which include neurological degeneration, inflammatory and immune responses, autoimmune diseases, diabetes, heart failure, atherosclerosis, response to infection, wound healing, liver, lung, and kidney disease. Gal-3 is known to regulate many biological activities including cell adhesion, angiogenesis, growth, apoptosis, migration, and metastasis. Rapamycin has been examined alone or in combination with other drugs for treatment of various cancers in clinical studies. Although it has shown promising therapeutic effects, its clinical development was interrupted by poor aqueous solubility and limited preferential distribution. To overcome these limitations, RA has been chemically modified to hydrophilic analogues, such as everolimus (EV). However, all these approaches can only partially increase the solubility, but has little effect on the blood distribution and pharmacokinetics. Therefore, it is necessary to explore other RA conjugates to improve aqueous solubility and tissue distribution profile. Recently we reported that RP-MPEG inhibits the growth of various cancer cell lines by acting on mammalian target of RP (mTOR) receptor site and it can be used for gastric cancer.
OBJECTIVE: To construct various molecular weight RP-MPEG by replacing MPEG chain in 40-O-(2- hydroxyethyl) position of the EV and analyze their binding affinity to Gal-3.
METHODS: The chemical structures of various molecular weight RP-MPEG were built using ChemSketch software. The molecular docking study was performed to find the best probable structure of RP-MPEG for competitive inhibition of the CRD, based on the interaction score. For that purpose, the 3D structures of RP and EV were obtained from NCBI PubChem compound database, where the structural protein-co-crystallized ligand complex of Gal-3 (TD2, as a native ligand) was retrieved from RCSB Protein Data Bank. All structures of the selected compounds, served as molecules for molecular modeling, were optimized through MOE.2014 software before docking. Hydrogen atoms and partial charges were added to the protein. Protein minimization was performed in gas solvation with the side chains, keeping it rigid and the ligand flexible. The selected site was isolated and minimized, followed by protonating the protein. The 3D ligands were minimized using MMFF94x with cutoffs of 10 to 12 Å. The hydrogens and charges were fixed, and the RMS gradient was set to 0.001 kcal/mol. The docking results were analyzed to identify and assess the binding affinity of these compounds to CRD using drug discovery software.
RESULTS: Our results indicated that RP-MPEG with MW 1178.51 g/mol has a logP value of 3.79 and has possessed the strongest binding affinity toward CRD of Gal-3 with a docking score of -6.87. Compared with TD2, there were additional close contacts for RP-MPEG (MW 1178.51 g/mol), coming from three hydrogen bonds with Asp148, Arg162, and Arg144 which suggest that this ligand is a strong competitive inhibitor among the other molecules for Gal-3.
CONCLUSION: RP-MPEG with the MW 1178.51 g/mol could be a promising blocker for various biological action of Gal-3 includes profibrotic activity, modulation of immune responses and inflammatory responses to cancer that contributes to neoplastic transformation, angiogenesis and metastasis. Other: The 95% confidence intervals (CIs) of the binding affinity (according to their mean and standard errors) were estimated with 2.5 and 97.5 percentile as the lower and upper bounds.
Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells

Maki MAA, Kumar PV, Cheah SC, Siew Wei Y, Al-Nema M, Bayazeid O, et al.

ACS Omega, 2019 May 31;4(5):8767-8777.
PMID: 31459966 DOI: 10.1021/acsomega.9b00109

Several studies have shown that the mammalian target of rapamycin (mTOR) inhibitor; everolimus (EV) improves patient survival in several types of cancer. However, the meaningful efficacy of EV as a single agent for the treatment of colorectal cancer (CRC) has failed to be proven in multiple clinical trials. Combination therapy is one of the options that could increase the efficacy and decrease the toxicity of the anticancer therapy. This study revealed that the β-cyclodextrin (β-CD):FGF7 complex has the potential to improve the antiproliferative effect of EV by preventing FGF receptor activation and by enhancing EV cellular uptake and intracellular retention. Molecular docking techniques were used to investigate the possible interaction between EV, β-CD, and FGF7. Molecular docking insights revealed that β-CD and EV are capable to form a stable inclusion complex with FGF at the molecular level. The aqueous solubility of the inclusion complex was increased (3.1 ± 0.23 μM) when compared to the aqueous solubility of pure EV (1.7 ± 0.16 μM). In addition, the in vitro cytotoxic activity of a FGF7:β-CD:EV complex on Caco-2 cell line was investigated using real-time xCELLigence technology. The FGF7:β-CD:EV complex has induced apoptosis of Caco-2 cells and shown higher cytotoxic activity than the parent drug EV. With the multitargets effect of β-CD:FGF7 and EV, the antiproliferative effect of EV was remarkably improved as the IC50 value of EV was reduced from 9.65 ± 1.42 to 1.87 ± 0.33 μM when compared to FGF7:β-CD:EV complex activity. In conclusion, the findings advance the understanding of the biological combinational effects of the β-CD:FGF7 complex and EV as an effective treatment to combat CRC.

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