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Vascular endothelial growth factor receptor-2 is a dynamic target for therapeutic intervention in various types of cancer. This study was aimed at exploring the VEGFR-2 inhibitory activity of a novel library of quinoxalin-2-one derivatives such as 3-furoquinoxaline carboxamides, 3-pyrazolylquinoxalines, and 3-pyridopyrimidyl-quinoxalines. Among them, 6c, 7a, and 7d-f produced remarkable cytotoxicity against HCT-116 (IC 50 's 4.28-9.31 µM) and MCF-7 (IC 50 's 3.57-7.57 µM) cell lines using the MTT assay and doxorubicin (DOX) as a reference standard. Interestingly, results of cytotoxicity towards the human fibroblast cell line WI38 revealed that these hits demonstrated higher selectivity indices towards both HCT-116 (SI 8.69-23.19) and MCF-7 (SI 9.48-27.80) than DOX, SI 0.72 and 0.90, respectively. Then, these hits were subjected to a mechanistic study; they showed direct inhibition of VEGFR-2. Impressively, compound 7f displayed 1.2 times the VEGFR-2 inhibitory activity of sorafenib. The antiangiogenic potential of 7f was proved via lowering the level of VEGF-A, than that of control. It as well, exhibited scratch closure percent of 61.8%, compared with 74.5% of control at 48 hrs, indicating the potential anti-migratory effect of the compound 7f. It significantly increased the expression of tumor suppressor gene (p53) on MCF-7 cells by almost 18 folds and upregulated the caspase-3 level by 10.7 folds, compared to the control. Cell cycle analysis revealed cell cycle arrest at G2/M together with a PreG increase which indicated apoptosis induction potential. Annexin V-FITC apoptosis results proposed the two modes of cell death (apoptosis and necrosis) as an inherent mechanism of cytotoxicity of compound 7f. Molecular docking further supported the mechanism showing the affinity of target compounds for VEGFR-2 active site. Moreover, physicochemical and drug-like properties were assessed from the ADME properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Marine algae have served as a treasure trove of structurally variable and biologically active metabolites. The present study emphasizes on UPLC-MS metabolites fingerprinting for the first systematic broad scale metabolites characterization of three different phyla of marine seaweeds; Ulva fasciata, Pterocladia capillacea and Sargassum hornschuchii along with Spirulina platensis harvested from the Mediterranean Sea. A total of 85 metabolites belonging to various classes including mostly fatty acids and their derivatives, terpenoids, amino acids and dipeptides with considerable amounts of polyphenolic compounds. OPLS-DA model offered a better overview of phylum-based discrimination rapidly uncovering the compositional heterogeneity in metabolite profiles of algae extracts. An OPLS model was constructed using the cytotoxic activities against PC3 and MDA-MB-231 tumor cells to succinctly screen cytotoxic discriminatory metabolites among the tested algae species. The coefficient plot revealed that unsaturated fatty acids as stearidonic acid and linolenic acid, terpenoids namely as rosmanol, campestanol, dipeptides primarily glutamylglycine, glycyltyrosine along with polyphenolic compounds being abundantly present in S. platensis and U. fasciata samples with relatively marked cytotoxic potential might be the significant contributors synergistically meditating their anti-proliferative activity against PC3 and MDA-MB-231 tumor cells. Such results serve as baseline for understanding the chemistry of these species and performing strict correlation between metabolite and activity where a lack of information in this regard is observed., (© 2022. The Author(s).)

Objective: To clinically assess the effectiveness of topical chamomile oral gel in the prevention of chemotherapy-induced oral mucositis., Material and Methods: A parallel single-blind randomized clinical trial conducted on 45 patients who were undergoing chemotherapy. Patients were assigned to three equal groups. Group I received conventional symptomatic treatment that included antifungal agents (Miconaz oral gel, Medical Union Pharmaceuticals), topical anesthetics, and anti-inflammatory agent (BBC oral spray, Amoun Pharmaceutical Company) three times per day for three weeks, group II received 3% chamomile topical oral gel, whereas group III patients were given both conventional symptomatic treatment and chamomile topical oral gel. All patients were clinically assessed for pain and oral mucositis severity at three separate time intervals: 1 week, 2 weeks, and 3 weeks., Results: Most patients experienced oral mucositis with more severity reported in the conventional group (grade III = 6.7%) compared to the other two groups, neither of which developed more than grade II. Mean pain scores showed no significant difference between the groups, but intragroup analysis showed that pain score increased in the conventional treatment group more than the other two groups., Conclusion: Topical chamomile 3% gel has demonstrated in this study to lower the severity of the mucositis with lower pain scores compared to the other two groups., (© 2020 Wiley Periodicals LLC.)

The discovery of the antiproliferative potential of tranilast prompted additional studies directed at understanding the mechanisms of tranilast action. Its inhibitory effect on cell proliferation depends principally on the capacity of tranilast to interfere with transforming growth factor beta (TGFβR1) signaling. This work summarizes design, synthesis and biological evaluation of sixteen novel tranilast analogs on different tumors such as PC-3, HepG-2 and MCF-7 cell lines. The in vitro cytotoxicity was evaluated using MTT assay showed that, twelve compounds out of sixteen showed higher cytotoxic activities (IC 50 's 1.1-6.29 µM), than that of the reference standard, 5-FU (IC 50 7.53 µM). The promising cytotoxic hits (4b, 7a, b and 14c-e), proved to be selective to cancer cells when their cytotoxicity's are examined on human normal cell line (WI-38). Then they are investigated for their possible mode of action as TGFβR1 inhibitors; remarkable inhibition of TGFβR1 by these hits was observed at the range of IC 50 0.087-3.276 μM. The cell cycle analysis of the most potent TGFβR1 inhibitor, 4b revealed cell cycle arrest at G 2 /M phase on prostate cancer cells. Additionally, it is clearly indicated apoptosis induction at Pre-G1 phase, this is substantiated by significant increase in the expression on the tumor suppressor gene, p53 and up regulation the level of apoptosis mediator, caspase-3. In addition, in silico study was performed for validating the physicochemical and ADME properties which revealed that, all compounds are orally bioavailable with no side effects complying with Lipinski rule. The proposed mode of action can be further explored on the light of molecular modeling simulation of the most potent compounds, 4b and 14e which were docked into the active sites of TGFβR1 to predict their affinities toward the receptor., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Adenosine Monophosphate-Activated Protein Kinase or AMPK is a highly-conserved master-regulator of numerous cellular processes, including: Maintaining cellular-energy homeostasis, modulation of cytoskeletaldynamics, directing cell growth-rates and influencing cell-death pathways. AMPK has recently emerged as a promising molecular target in cancer therapy. In fact, AMPK deficiencies have been shown to enhance cell growth and proliferation, which is consistent with enhancement of tumorigenesis by AMPK-loss. Conversely, activation of AMPK is associated with tumor growth suppression via inhibition of the Mammalian Target of Rapamycin Complex-1 (mTORC1) or the mTOR signal pathway. The scientific communities' recognition that AMPK-activating compounds possess an anti-neoplastic effect has contributed to a rush of discoveries and developments in AMPK-activating compounds as potential anticancer-drugs. One such example is the class of compounds known as Biguanides, which include Metformin and Phenformin. The current review will showcase natural compounds and their derivatives that activate the AMPK-complex and signaling pathway. In addition, the biology and history of AMPK-signaling and AMPK-activating compounds will be overviewed, their anticancer-roles and mechanisms-of-actions will be discussed, and potential strategies for the development of novel, selective AMPK-activators with enhanced efficacy and reduced toxicity will be proposed.