Red Sea Sponge Callyspongia siphonella Extract Induced Growth Inhibition and Apoptosis in Breast MCF-7 and Hepatic HepG-2 Cancer Cell Lines in 2D and 3D Cell Cultures.

Introduction: The increasing incidence of cancer diseases necessitates the urgent exploration of new bioactive compounds. One of the trends in drug discovery is marine sponges which is gaining significant support due to the abundant production of natural pharmaceutical compounds obtained from marine ecosystems. This study evaluates the anticancer properties of an organic extract from the Red Sea sponge Callyspongia siphonella (C. siphonella) on HepG-2 and MCF-7 cancer cell lines. Methods: C. siphonella was collected, freeze-dried, and extracted using a methanol-dichloromethane mixture. The extract was analyzed via Liquid Chromatography-Mass Spectrometry. Cytotoxic effects were assessed through cell viability assays, apoptosis detection, cell cycle analysis, mitochondrial membrane potential assays, scratch-wound healing assays, and 3D cell culture assays. Results: Fifteen compounds were identified in the C. siphonella extract. The extract showed moderate cytotoxicity against MCF-7 and HepG-2 cells, with IC50 values of 35.6 ± 6.9 µg/mL and 64.4 ± 8 µg/mL, respectively, after 48 hours of treatment. It induced cell cycle arrest at the G2/M phase in MCF-7 cells and the S phase in HepG-2 cells. Apoptosis increased significantly in both cell lines, accompanied by reduced mitochondrial membrane potential. The extract inhibited cell migration, with notable reductions after 24 and 48 hours. In 3D cell cultures, the extract had IC50 values of 5.1 ± 2 µg/mL for MCF-7 and 166.4 ± 27 µg/mL for HepG-2 after 7 days of treatment, showing greater potency in MCF-7 spheres compared to HepG-2 spheres. Discussion and Conclusion: The anticancer activity is attributed to the bioactive compounds. The C. siphonella extract's ability to induce apoptosis, disrupt mitochondrial membrane potential, and arrest the cell cycle highlights its potential as a novel anticancer agent. Additional research is required to investigate the underlying mechanism by which this extract functions as a highly effective anticancer agent.

Ziziphus spina-christi L. extract attenuates bleomycin-induced lung fibrosis in mice via regulating TGF-ß1/SMAD pathway: LC-MS/MS Metabolic profiling, chemical composition, and histology studies.

Ancient Egyptians (including Bedouins and Nubians) have long utilized Ziziphus spina-christi (L.), a traditional Arabian medicinal herb, to alleviate swellings and inflammatory disorders. It is also mentioned in Christian and Muslim traditions. Ziziphus spina-christi L. (Family: Rhamnaceae) is a plentiful source of polyphenols, revealing free radical scavenging, antioxidant, metal chelating, cytotoxic, and anti-inflammatory activities. Herein, different classes of the existing bioactive metabolites in Z. spina-christi L. were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the first time. The study also aimed to assess the anti-inflammatory and antifibrotic properties of Z. spina-christi L. extract against bleomycin-induced lung fibrosis in an experimental mouse model. 32 male Swiss Albino mice were assigned into 4 groups; the first and second were the normal control group and the bleomycin positive control (single 2.5 U/kg bleomycin intratracheal dose). The third and fourth groups received 100 and 200 mg/kg/day Z. spina-christi L. extract orally for 3 weeks, 2 weeks before bleomycin, and 1 week after. The bioactive metabolites in Z. spina-christi L. extract were identified as phenolic acids, catechins, flavonoids, chalcones, stilbenes, triterpenoid acids, saponins, and sterols. The contents of total phenolic compounds and flavonoids were found to be 196.62 mg GAE/gm and 33.29 mg QE/gm, respectively. In the experimental study, histopathological examination revealed that lung fibrosis was attenuated in both Z. spina-christi L.- treated groups. Z. spina-christi L. extract downregulated the expression of nuclear factor kappa B (NF-κB) p65 and decreased levels of the inflammatory markers tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and c-Jun N-terminal kinase (JNK) in lung tissue. Z. spina-christi L. also downregulated the expression of the fibrotic parameters collagen-1, alpha-smooth muscle actin (α-SMA), transforming growth factor-beta 1 (TGF-ß1), matrix metalloproteinase-9 (MMP-9) and SMAD3, with upregulation of the antifibrotic SMAD7 in lung tissue. Overall, the present study suggests a potential protective effect of Z. spina-christi L. extract against bleomycin-induced lung fibrosis through regulation of the TGF-ß1/SMAD pathway.

Design, Synthesis and Anticancer Evaluation of New 1-allyl-4-oxo-6-(3,4,5- trimethoxyphenyl)-1,4-dihydropyrimidine-5-carbonitrile Bearing Pyrazole Moieties.

AIM: pyrimidine and pyrazole have various biological and pharmaceutical applications such as antibacterial, antifungal, antileishmanial, anti-inflammatory, antitumor, and anti-cancer. INTRODUCTION: In this search, the goal is to prepare pyrimidine-pyrazoles and study their anticancer activity. METHODS: 1-allyl-4-oxo-6-(3,4,5-trimethoxyphenyl)-1,4-dihydropyrimidine-5-carbonitrile bearing pyrazoles (4,6-8) have been synthesized. Firstly, the reaction of 1-allyl-2-(methylthio)-4-oxo-6- (3,4,5-trimethoxyphenyl)-1,4-dihydropyrimidine-5-carbonitrile (1) with chalcones 2a-b produced the intermediates 3a-b. The latter was reacted with hydrazine hydrate to give the targets 4a-b. On the other hand, hydrazinolysis of compound 1 yielded the hydrazino derivative 5 which upon reaction with chalcones 2c-i or 1,3-bicarbonyl compounds afforded the compounds 6-8. Finally, the new compounds were characterized by spectral data (IR, 1H NMR, 13C NMR) and elemental analysis. Moreover, they were evaluated for Panc-1, MCF-7, HT-29, A-549, and HPDE cell lines as anticancer activity. RESULTS: All the tested compounds 3,4,6-8 showed IC50 values > 50 µg/mL against the HPDE cell line. Compounds 6a and 6e exhibited potent anticancer activity where the IC50 values in the range of 1.7- 1.9, 1.4-182, 1.75-1.8, and 1.5-1.9 µg/mL against Panc-1, MCF-7, HT-29, and A-549 cell lines. CONCLUSION: New pyrimidine-pyrazole derivatives were simply synthesized, in addition, some of them showed potential anticancer activity.

Molecular and Biological Investigation of Isolated Marine Fungal Metabolites as Anticancer Agents: A Multi-Target Approach.

Cancer is the leading cause of death globally, with an increasing number of cases being annually reported. Nature-derived metabolites have been widely studied for their potential programmed necrosis, cytotoxicity, and anti-proliferation leading to enrichment for the modern medicine, particularly within the last couple of decades. At a more rapid pace, the concept of multi-target agents has evolved from being an innovative approach into a regular drug development procedure for hampering the multi-fashioned pathophysiology and high-resistance nature of cancer cells. With the advent of the Red Sea Penicillium chrysogenum strain S003-isolated indole-based alkaloids, we thoroughly investigated the molecular aspects for three major metabolites: meleagrin (MEL), roquefortine C (ROC), and isoroquefortine C (ISO) against three cancer-associated biological targets Cdc-25A, PTP-1B, and c-Met kinase. The study presented, for the first time, the detailed molecular insights and near-physiological affinity for these marine indole alkaloids against the assign targets through molecular docking-coupled all-atom dynamic simulation analysis. Findings highlighted the superiority of MEL's binding affinity/stability being quite in concordance with the in vitro anticancer activity profile conducted via sulforhodamine B bioassay on different cancerous cell lines reaching down to low micromolar or even nanomolar potencies. The advent of lengthy structural topologies via the metabolites' extended tetracyclic cores and aromatic imidazole arm permitted multi-pocket accommodation addressing the selectivity concerns. Additionally, the presence decorating polar functionalities on the core hydrophobic tetracyclic ring contributed compound's pharmacodynamic preferentiality. Introducing ionizable functionality with more lipophilic characters was highlighted to improve binding affinities which was also in concordance with the conducted drug-likeness/pharmacokinetic profiling for obtaining a balanced pharmacokinetic/dynamic profile. Our study adds to the knowledge regarding drug development and optimization of marine-isolated indole-based alkaloids for future iterative synthesis and pre-clinical investigations as multi-target anticancer agents.

Synthesis, Antimicrobial, Anti-Virulence and Anticancer Evaluation of New 5(4H)-Oxazolone-Based Sulfonamides.

Since the synthesis of prontosil the first prodrug shares their chemical moiety, sulfonamides exhibit diverse modes of actions to serve as antimicrobials, diuretics, antidiabetics, and other clinical applications. This inspiring chemical nucleus has promoted several research groups to investigate the synthesis of new members exploring new clinical applications. In this study, a novel series of 5(4H)-oxazolone-based-sulfonamides (OBS) 9a-k were synthesized, and their antibacterial and antifungal activities were evaluated against a wide range of Gram-positive and -negative bacteria and fungi. Most of the tested compounds exhibited promising antibacterial activity against both Gram-positive and -negative bacteria particularly OBS 9b and 9f. Meanwhile, compound 9h showed the most potent antifungal activity. Moreover, the OBS 9a, 9b, and 9f that inhibited the bacterial growth at the lowest concentrations were subjected to further evaluation for their anti-virulence activities against Pseudomonas aeruginosa and Staphylococcus aureus. Interestingly, the three tested compounds reduced the biofilm formation and diminished the production of virulence factors in both P. aeruginosa and S. aureus. Bacteria use a signaling system, quorum sensing (QS), to regulate their virulence. In this context, in silico study has been conducted to assess the ability of OBS to compete with the QS receptors. The tested OBS showed marked ability to bind and hinder QS receptors, indicating that anti-virulence activities of OBS could be due to blocking QS, the system that controls the bacterial virulence. Furthermore, anticancer activity has been further performed for such derivatives. The OBS compounds showed variable anti-tumor activities, specifically 9a, 9b, 9f and 9k, against different cancer lines. Conclusively, the OBS compounds can serve as antimicrobials, anti-virulence and anti-tumor agents.

Celastrol Modulates Multiple Signaling Pathways to Inhibit Proliferation of Pancreatic Cancer via DDIT3 and ATF3 Up-Regulation and RRM2 and MCM4 Down-Regulation.

BACKGROUND: Pancreatic cancer is one of the most serious and lethal human cancers with a snowballing incidence around the world. The natural product celastrol has also been widely documented as a potent anti-inflammatory, anti-angiogenic, and anti-oxidant. PURPOSE: To elucidate the antitumor effect of celastrol on pancreatic cancer cells and its modulatory role on whole genome expression. METHODS: The antitumor activity of celastrol on a panel of pancreatic cancer cells has been evaluated by Sulforhodamine B assay. Caspase 3/7 and histone-associated DNA fragments assays were done for apoptosis measurement. Additionally, prostaglandin (PGE2) inhibition was evaluated. Moreover, a microarray gene expression profiling was carried out to detect possible key players that modulate the antitumor effects of celastrol on cells of pancreatic cancer. RESULTS: Our findings indicated that celastrol suppresses the cellular growth of pancreatic cancer cells, induces apoptosis, and inhibits PGE2 production. Celastrol modulated many signaling genes and its cytotoxic effect was mainly mediated via over-expression of ATF3 and DDIT3, and down-expression of RRM2 and MCM4. CONCLUSION: The current study aims to be a starting point to generate a hypothesis on the most significant regulatory genes and for a full dissection of the celastrol possible effects on each single gene to prevent the pancreatic cancer growth.