Mohamed A. Elkady

VEGFR-2 is a significant target in cancer treatment, inhibiting angiogenesis and impeding tumor growth. Utilizing the essential pharmacophoric structural properties, a new semi-synthetic theobromine analogue (T-1-MBHEPA) was designed as VEGFR-2 inhibitor. Firstly, T-1-MBHEPA's stability and reactivity were indicated through several DFT computations. Additionally, molecular docking, MD simulations, MM-GPSA, PLIP, and essential dynamics (ED) experiments suggested T-1-MBHEPA's strong binding capabilities to VEGFR-2. Its computational ADMET profiles were also studied before the semi-synthesis and indicated a good degree of drug-likeness. T-1-MBHEPA was then semi-synthesized to evaluate the design and the in silico findings. It was found that, T-1-MBHEPA inhibited VEGFR-2 with an IC₅₀ value of 0.121 ± 0.051 µM, as compared to sorafenib which had an IC₅₀ value of 0.056 µM. Similarly, T-1-MBHEPA inhibited the proliferation of HepG2 and MCF7 cell lines with IC₅₀ values of 4.61 and 4.85 µg/mL respectively - comparing sorafenib's IC₅₀ values which were 2.24 µg/mL and 3.17 µg/mL respectively. Interestingly, T-1-MBHEPA revealed a noteworthy IC₅₀ value of 80.0 µM against the normal cell lines exhibiting exceptionally high selectivity indexes (SI) of 17.4 and 16. 5 against the examined cell lines, respectively. T-1-MBHEPA increased the percentage of apoptotic MCF7 cells in early and late stages, respectively, from 0.71 % to 7.22 % and from 0.13 % to 2.72 %, while the necrosis percentage was increased to 11.41 %, in comparison to 2.22 % in control cells. Furthermore, T-1-MBHEPA reduced the production of pro-inflammatory cytokines TNF-α and IL-2 in the treated MCF7 cells by 33 % and 58 %, respectively indicating an additional anti-angiogenic mechanism. Also, T-1-MBHEPA decreased significantly the potentialities of MCF7 cells to heal and migrate from 65.9 % to 7.4 %. Finally, T-1-MBHEPA’s oral treatment didn’t show toxicity on the liver function (ALT and AST) and the kidney function (creatinine and urea) levels of mice.

Colorectal cancer is one of the most invaded lethal types of malignancy worldwide. It’s an important issue to find prophylactic and curative agents against that life-threatening ailment, preferably from cheap, natural, commonly available nutraceuticals. Herein, total pomegranate peel extract was tested for its significance as an anticancer agent against bacterial pathogens-induced colon cancer in mice model. The phytochemical investigation was carried out via quantitative estimation of phenolic and flavonoid contents along with metabolomic analysis. In this study, Bagg Albino/c (BALB/c) mice were classified into 4 groups including negative control group, untreated mice with pathogen-induced colon cancer group, mice treated with 5-flurouracil and mice treated pomegranate peels extract (PPE). B cell lymphoma gene 2 (BCL2) and hypoxia-inducible factor 1 -α (HIF1-α) proteins were measured using enzyme-linked immunosorbent assay (ELISA) kits in all groups. Histopathological changes occurred in the colon of 4 groups were evaluated. The bioactive extract was found to possess a potent antioxidant capacity (357.6 ± 0.5 and 408.4 ± 0.55 mg Trolox equivalents/g) for 1, 1-Diphenyl-2-picryl-hydrazyl (DPPH) and 2, 2‵-azinobis-3-ethylbenzothiazoline-6-sulfonate (ABTS) assays, respectively, owing to its high amount of phenolic acids (174.0±0.65) mg gallic acid equivalent/g and flavonoids (23.2 ±0.3 mg catechin equivalent/g). Furthermore, metabolomics investigation by liquid chromatography/electrospray ionization - tandem mass spectrometry (LC-ESI-MS/MS) analysis revealed the identification of 73 metabolites from varying chemical classes, most abundantly gallotannin and ellagitannin derivatives, flavonoids and their glycosides, pentacyclic triterpenes, coumarins, in addition to many phenolic and fatty acids. In vivo experiment, the metabolomics investigation by gas chromatography - mass spectrometry (GC-MS) revealed a decrease in 1H-indole-3-acetic acid and heptanedioic acid in mice treated PPE compared with untreated mice with pathogen-induced colon cancer group. Moreover, an increase in benzoic acid, alanine, phenylalanine, and glucose were observed in mice treated PPE compared with untreated mice. Finally, reduction in of BCL2 and HIF1-α serum levels in treated groups compared to untreated group. PPE showed anticancer activity against bacterial pathogen-induced colon cancer in vivo via reduction of serum levels of BCL2 and HIF1-α as apoptosis controlling factors leading to histopathological improvement of colon of PPE treated group.