Anticancer Candidates Research Articles

Synthesis, Characterization and Biological Evaluation of New Enamide Fluorinated‐Schiff Base Derivatives as Potential Cytotoxic and Apoptosis‐Inducing Agents

AbstractIn search for new anticancer candidates, a new series of enamide fluorinated‐Schiff base derivatives were synthesized and confirmed by spectroscopic techniques as well as elemental microanalyses. The newly prepared compounds were evaluated for their cytotoxic activity on MCF‐7 breast adenocarcinoma cell line. The benzaldehyde Schiff base and furfural Schiff base derivatives (IC50=3.67±0.15 and 2.06±0.08 μM, respectively) were found to be the most potent molecules of all the tested derivatives against the MCF‐7 cancer cells. Additionally, the furfural Schiff base compound was more potent than colchicine by 1.74‐fold, while benzaldehyde Schiff base compound was nearly equipotent with colchicine as standard drug. In addition to tubulin inhibition activity, enamide‐furfural Schiff base molecule caused cell cycle arrest in MCF‐7 cells at the G2/M phase (2.62‐fold more than control MCF‐7) and induced apoptotic death (48.97‐fold compared to untreated MCF‐7 control) as indicated by FACS analysis. Furthermore, apoptotic studies conducted by enamide‐furfural Schiff base derivative were accomplished by downregulation of mitochondrial membrane potential by 1.56‐fold relative to control untreated cells.

Nanocomposites of iron oxide, sodium alginate, and eugenol induce apoptosis via PI3K/Akt/mTOR signaling in Hep3 cells and in vivo hepatotoxicity in the zebrafish model

Hepatic cancer is among the most recurrently detected malignancies worldwide and one of the main contributors to cancer-associated mortality. With few available therapeutic choices, there is an instant necessity to explore suitable options. In this aspect, Nanotechnology has been employed to explore prospective chemotherapeutic approaches, especially for cancer treatment. Nanotechnology is concerned with the biological and physical properties of nanoparticles in the therapeutic use of drugs. In the current work, formulation, and characterization of α-Fe2O3–Sodium Alginate-Eugenol nanocomposites (FSE NCs) using several approaches like SEM and TEM, UV–visible, FTIR, and PL spectroscopy, XRD, EDAX, and DLS studies have been performed. With an average size of 50 nm, the rhombohedral structure of NCs was identified. Further, their anticancer activity against Hep3B liver cancer cell lines has been performed by cell viability, dual staining, DCFH-DA, Annexin-V/-FITC/PI, cell cycle analysis methods, and PI3K/Akt/mTOR signaling proteins were studied to assess the anticancer effects of the NCs in Hep3B cells. Also, anti-cancer activity on animal modeling in-vivo using zebra fishes to hematological parameters, liver enzymes, and histopathology study effectiveness was noticed. Moreover, the NCs reduced the viability, elevated the ROS accumulation, diminished the membrane integrity, reduced the antioxidants, blocked the cell cycle, and triggered the PI3K/Akt/mTOR signaling axis that eventually resulted in cell death. As a result, FSE NCs possess huge potential for use as a possible anticancer candidate.

The design and virtual screening of thiourea derivatives as a Sirtuin-1 inhibitor

The SIRT1 is overexpressed in a number of cancers. As a result, inhibiting SIRT1 may be used as a cancer treatment technique. Modification of 1-benzoyl-3-methylthiourea derivatives was carried out in this study by changing the aromatic side. The designed compounds (94) were subjected to in silico docking, pharmacokinetics, and preclinical testing. In the docking sample, the (4-decyl-N-(methylcarbamothioyl)benzamide (91), 2-(benzyloxy)-N-(methylcarbamo-thioyl)benzamide (93) and N-(methylcarbamothioyl)-2-naphthamide (94) were predicted to display better inhibition of SIRT1, so they were chosen for subsequent molecular dynamic studies. The compound 93 is proposed as a possible anticancer candidate that inhibits SIRT1 based on the screening results from molecular docking, pharmacokinetic predictions, and molecular dynamics.

Design and Synthesis of C-8 spiro-isoxazoline analogues of 14-Deoxy-11,12-didehydroandrographolide (14-DDA) for dual targeting of CDK4 and BCL2 mediated anticancer activity

14-Deoxy-11,12-didehydroandrographolide (14-DDA, 3), a secondary metabolite found in Andrographis paniculata nees, has been synthetically modified into a new series of C-8 spiro-isoxazoline derivatives. Andrographolide and its derivatives were well reported for the anticancer activity so herein we have synthesised C-8 spiro-isoxazoline derivatives (4a-l) and screened for in vitro studies against four human cancer cell lines: breast (MCF-7), lung (A549), pancreatic (MiaPaCa-2), and prostate (PC-3). Most of the synthesized compounds exhibited better anti-cancer activities than the parent natural products andrographolide (1) and 14-deoxy-11,12-didehydroandrographolide (3) for different human cancer lines. Among all compounds, compound 4k displayed most potent cytotoxicity (IC50 =3 μM) in breast cancer cells (MCF-7). Further, mechanistic studies revealed that compound 4k affected the nuclear morphology of MCF-7 cells, increased the production of cellular and mitochondrial ROS, decreased the mitochondrial membrane potential (MMP), and inhibited the colony formation. The compound 4k also induced apoptosis in MCF-7 by attenuating the BCl2 expression in a dose dependent manner. The expression of Cdk-4 was also downregulated by 4k. The overall findings of this study indicate that the compound 4k exhibited significant anticancer activity with reduced toxicity in-vitro and might thus be a promising anti-cancer lead candidate.

CONFORMATIONAL STUDY OF MOLECULES IN A BIOLOGICAL ENVIRONMENT, DESIGN OF INHIBITORS OF HUMAN AMINOPEPTIDASE M1 IMPLICATED IN CANCER THERAPY

Objective: A novel subnanomolar anticancer hydroxamic acid containing drug candidates, inhibitors of human M1 aminopeptidase (APN) a recent validated target and has reached the predicted subnanomolar range of inhibitory potency. Methods: A quantitative structure activity relationships (QSAR) complexation model has been developed from a compounds of 37 hydroxamic acid derivatives (AHD1-37 as training set, TS) to establish a linear correlation between the calculated relative Gibbs free energies (GFE: ΔΔGcom) of APN-AHDx complex formation and the experimental inhibition potency (Kiexp). The predictive power of the QSAR model was then validated first with 9 other AHDs not included in the TS and thereafter with the generation of a 3D-QSAR-PH4 pharmacophore (PH4) model to screen the AHD chemical subspace built as a virtual combinatorial library of more than 58,644 AHD analogs). Finally the best PH4 hits were evaluated with the initial QSAR model for predicted potency (Kipre) and pharmacokinetic profile. Results: The QSAR model linear correlation equation: pKiexp=-0.1901×∆∆Gcom + 8.2886 , R2=0.94, the subsequent PH4 model linear correlation between experiment and PH4-estimated Ki: pKiexp=1.0006× pKipre + 0.0028, R2=0.79 documents the high predictive power of this approach. Finally the screening of the virtual library of AHD analogs yielded 95 orally bioavailable candidates the best reaching a predicted potency (Kipre) of 50 pM and displaying favorable pharmacokinetic profile. Conclusion: The combined use of molecular modeling (QSAR) and in silico PH4-based screening of the hypothetical combinatorial library has resulted in proposed and predicted potent anticancer candidates with a suitable pharmacokinetic profile. Peer Review History: Received: 3 August 2023; Revised: 12 September; Accepted: 25 October, Available online: 15 November 2023 Academic Editor: Dr. Nuray Arı, Ankara University, Turkiye, ari@ankara.edu.tr Received file: Reviewer's Comments: Average Peer review marks at initial stage: 7.0/10 Average Peer review marks at publication stage: 9.0/10 Reviewers: Prof. Hassan A.H. Al-Shamahy, Sana'a University, Yemen, shmahe@yemen.net.ye Prof. Dr. A. Hakan AKTAŞ, Süleyman Demirel University, Faculty of Science and Art, Department of Chemistry, Isparta-Turkey, hakanaktas@sdu.edu.tr

Therapeutic properties, biological effects, antiliver cancer, and anticolon cancer effects of some natural compounds: A biochemical approach.

Natural compounds, such as carotenoids, flavonoids, anthocyanins, or terpenoids, are physiologically active components found in plants (pigments), often known as phytochemicals or phytonutrients. The in vitro cytotoxic and anticolon cancer effects of biologically bavachin, bavachinin, artepillin C, and aromadendrin compounds against SW48, SNU-C1, COLO 205, RKO, LS411N, and SW1417 cancer cell lines were assessed. Results of enzymes and antibacterial, antifungal were in level of micromolar that is good impacts. These natural compounds may be antidiabetic, anticancer, and antibacterial candidates for drug design. IC50 results were obtained between 14-19 and 5-119 µM for α-amylase and α-glucosidase, respectively. Good inhibitor Bavachinin was detected for both enzymes (IC50 for α-amylase: 14.37 µM and IC50 for α-glucosidase: 5.27 µM). The chemical activities of aromadendrin, artepillin C, bavachin, and bavachinin against pancreatic α-amylase and α-glucosidase were assessed by conducting the molecular docking study. The chemical activities of aromadendrin, artepillin C, bavachin, and bavachinin against some of the expressed surface receptor proteins (CD44, CD47, CXCR4, EGFR, folate receptor, HER2, and endothelin receptor) in the mentioned cell lines were investigated using the molecular docking calculations. The results illustrated the atomic-level properties and potential interactions. These chemicals have high binding affinities to the enzymes and proteins, according to the docking scores. In addition, the compounds formed strong contacts with the enzymes and receptors. Thus, these compounds could be potential inhibitors for enzymes and cancer cells.

Synthesis and Computational Study of Bis-(1-(3-Chlorobenzoyl)-3-Phenylthiourea) Cobalt (III) as Anticancer Candidate

Cancer is a disease characterized by cells forming abnormally so that a buildup can cause lumps. Drug compounds used for anticancer treatment by chemotherapy become a severe problem because they have dangerous side effects and can affect patient’s quality of life. This study aims to discover new drug compounds with lowered toxicity effects. This was achieved by modifying their structures through synthesis, characterization, and estimating the interactions of the synthesized compounds with specific target receptors, utilizing a docking method. The result obtained was a synthesis yield of 36.2%. The characterization of complex compounds was characterized by the presence of a maximum wavelength of 273 nm and a molecular weight of 652 g/mmol, indicating the absorption of Co-O and Co-S at respective wavenumbers of 498 cm-1 and 604 cm- 1. The docking results showed that the Bis-(1-(3-Chlorobenzoyl)-3-Phenylthiourea) Cobalt (III) complex had the best activity on human estrogen receptor alpha (hER alpha) with a binding affinity value of - 9.40 kcal/mol and an inhibition constant of 0.129 M, which was lower than the comparison compound (cisplatin) and had a better pharmacokinetic profile than cisplatin. This study shows that the Bis-(1-(3-Chlorobenzoyl)-3-Phenylthiourea) Cobalt (III) complex is predicted to have potential as an anticancer candidate.

In vitro antiproliferative potential of Cassia angustifolia extracts on HepG2 cells to combat liver cancer

Liver cancer is a terrifying disease with limited treatment options and is responsible for global health and economic burden. Most anticancer options have severe adverse effects, including non-specific modes of action that aggravate the challenges of exploring effective, safe, and economical therapeutic sources. The current study aimed to decipher the cytotoxicity of ethanol (ECA) and n-hexane (HCA) extracts of a potential medicinal plant Cassia angustifolia on human liver cancer (HepG2) and noncancer human embryonic kidney (HEK-293) cells. Cassia angustifolia extracts were investigated first to profile phytocompounds through gas chromatography-mass spectrometry (GC-MS). Varying concentrations of C. angustifolia extract (10, 50, 100, 200, and 400 µg/mL) were evaluated for cytotoxicity through the MTT assay, cell viability assay, and morphological examination using a Floid cellular imaging station. Results of GC-MS analysis identified 45 compounds in ECA and HCA extracts, from which 10 compounds were common in both extracts. Most of them are reported to have antiproliferative activity. The ECA and HCA extracts showed potent cytotoxicities (IC50= 62 and 67 µg/mL) in HepG2 cells, while minimal effects on noncancer HEK-293T cells (IC50= 245 and 482 µg/mL) were recorded. The viability of cancer (HepG2) cells was calculated to be 98%, 79%, 45%, 30%, and 25% for ECA and 95%, 68%, 55%, 40%, and 31% for HCA extract, respectively. Significant percent viabilities on noncancer (HEK293T) cells were observed to be 95%, 90%, 88%, 76%, and 61% with ECA extract, and 97%, 95%, 88%, 75%, and 62% with HCA extract compared to those of untreated (UT) (100%) and DMSO (100%) treated cells. Cisplatin (positive control) exhibited ˂40% and ˂38% viabilities of cancer and normal cells, respectively. Morphological examination revealed that proliferation was reduced at 100, 200, and 400 μg/mL of the ECA extract and 200 and 400 μg/mL of the HCA extract on HepG2 cells. The HEK-293T cells did not show a noticeable decrease in viability by both extracts. In conclusion, C. angustifolia extracts showed considerable anticancer activity due to bioactive phytocompounds and were comparable to cisplatin (an FDA-approved drug). After further isolation and validation, identified phytocompounds can be available as safer anticancer candidates against liver cancer.

Targeting PPARγ/ NF-κB Signaling Pathway by Britannin, a Sesquiterpene Lactone from Inula aucheriana DC., in Gastric Cancer.

Gastric cancer is one of the most common and deadliest malignancies in the world. Therefore, there is an urgent need to develop new and effective agents to reduce mortality. The plants of genus Inula have gained the attention of researchers worldwide as a rich source of potent medicinal compounds. This study explores the anti-cancer activity of Britannin, a sesquiterpene lactone isolated from Inula aucheriana DC., and its molecular mechanism in gastric cancer cells, AGS and MKN45. Cytotoxicity was evaluated through the MTT assay following 24 h, 48 h, and 72 h treatment with different concentrations of Britannin. Apoptosis rate and caspase-3 activity were measured 24 h after treatment by Britannin. . Western blotting was performed to determine the expression of the NF-κB, IκBα, and PPARγ proteins. Moreover, quantitative RT-PCR was applied to measure the expression of NF-κB target genes. We showed that Britannin induced cell growth inhibition and apoptosis in gastric cancer cells. Britannin caused an elevation in mRNA and protein levels of PPARγ. The involvement of PPARγ was more confirmed using GW9662, a PPARγ inhibitor. Suppression of NF-κB was demonstrated by western blot analysis. Down-regulation of MMP-9, TWIST-1, COX-2, and Bcl-2 and up-regulation of Bax were also observed in gastric cancer cells. These results imply that activation of the PPARγ signaling pathway through suppression of NF-κB underlies the anti-cancer properties of Britannin in gastric cancer. Therefore, Britannin could be considered as a promising anti-cancer candidate for further evaluation.

QSAR study of benzylidene hydrazine benzamides derivatives with in vitro anticancer activity against human lung cancer cell line A459

Context: In the last decade, resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in lung cancer cases has been widespread. The discovery and development of new drugs need to be done to overcome the case. Aims: To develop lung anticancer candidates with benzylidene hydrazine benzamides derivatives that can inhibit the growth of human lung cancer cell line A459. Methods: The in silico approach method, along with the QSAR technique, plays an important role in the process of discovery and development of new drugs. In this study, we focused on developing benzylidene hydrazine benzamides derivatives that are much more potent by making the best QSAR equation of 11 benzylidene hydrazine benzamides that have been tested in vitro for its anticancer activity against human lung cancer cell line A459. Results: The best QSAR equation was obtained from benzylidene hydrazine benzamides derivatives as anticancer activity against human lung cancer cell line A459, with PIC50 = 0.738 (± 0.217) Log S - 0.031 (± 0.007) rerank + 0.017 (± 0.016) MR -1.359 ± (1.381) (n = 11; Sig = 0.003; r = 0.921; R2 = 0.849; F= 13.096; Q2 = 0.61). Conclusions: The best QSAR equation can be a tool to obtain a new chemical structure model with more potential and reduce trials and errors.

In vitro cytotoxicity evaluation of organotin(IV) complexes derived from bisphosphoramide ligand: DNA binding and molecular docking studies

Considering the valuable position of organotins and the biotic role of phosphorus compounds in biological processes, in this research work, we investigated and introduced a new class of anticancer candidates based on organotin(IV) complexes derived from bisphosphoramide ligands. Four selected complexes were prepared from the reaction of SnMe2Cl2 (C1), SnBu3Cl (C2), SnPh2Cl2 (C3), and SnPh3Cl (C4) metal salts with piperazine-1,4-diylbis(diphenylphosphine oxide) ligand (LP). The newly synthesized complexes were characterized using spectroscopic techniques. Single crystal of C1 structure was determined by X-ray crystallography. Binding potentials of compounds to DNA were also explored using electron absorption titration and competitive fluorescence quenching techniques, which indicated that complexes and CT-DNA strongly interacted. Cytotoxicity assay of compounds against triple-negative human breast cancer (MDA-MB-231) cells proved that three complexes C2, C3, and C4 had a very considerable impact on the reduced viability of cancer cells and among them, C4 revealed the maximum anticancer activity (IC50 = 0.35 ± 1.18 µg/mL, 0.28 µM) in comparison to reference cisplatin drug (IC50 = 19 µM). Furthermore, the analysis and comparison of the orientations and reactive sites of the compounds using molecular docking simulation, pharmacophore, and NCI studies further confirmed the significant effects of the type and number of aryl and alkyl substituents on the biological activities.

Rational design and eco-friendly one-pot multicomponent synthesis of novel ethylidenehydrazineylthiazol-4(5H)-ones as potential apoptotic inducers targeting wild and mutant EGFR-TK in triple negative breast cancer

A novel series of ethylidenehydrazineylthiazol-4(5H)-ones were synthesized using various eco-friendly one-pot multicomponent synthetic techniques. The anticancer activity of compounds (4a-m) was tested against 11 cancer cell lines. While the IC50 of all compounds was evaluated against the most sensitive cell lines (MDA-MB-468 and FaDu). Our SAR study pinpointed that compound 4a, having a phenyl substituent, exhibited a significant growth inhibition % against all cancer cell lines. The frontier anticancer candidates against the MDA-MB-468 were also examined against the wild EGFR (EGFR-WT) and mutant EGFR (EGFR-T790M) receptors. Most of the synthesized compounds exhibited a higher inhibitory potential against EGFR-T790M than the wild type of EGFR. Remarkably, compound 4k exhibited the highest inhibitory activity against both EGFR-WT and EGFR-T790M with IC50 values (0.051 and 0.021 µM), respectively. The pro-apoptotic protein markers (p53, BAX, caspase 3, caspase 6, caspase 8, and caspase 9) and the anti-apoptotic key marker (BCL-2) were also measured to propose a mechanism of action for the compound 4k as an apoptotic inducer for MDA-MB-468. Investigation of the cell cycle arrest potential of compound 4k was also conducted on MDA-MB-468 cancer cells. We also evaluated the inhibitory activities of compounds (4a-m) against both EGFR-WT and EGFR-T790M using two different molecular docking processes.

Exploration of efficacy, cellular responses, and safety profile of novel 9-(3-Pyridyl) noscapine derivatives as promising anticancer candidates

This study presented a novel derivative of the antitussive compound noscapine, named 9-3-Pyridyl noscapine (PYNos), to enhance its anticancer potential. Through in silico investigations, PYNos exhibited strong interactions with microtubules, inhibiting cancer cell proliferation both alone and in combination with docetaxel. Docking scores highlighted the affinity of PYNos −5.67 kcal/mol and docetaxel −4.94 kcal/mol to microtubules. When docked with tubulin-DOX co-complex, PYNos displayed a synergistic score of −8.99 kcal/mol. MTT assays on MCF-7 breast cancer cells showed PYNos IC50 values of 11.0 µM (48 h) and 8.4 µM (72 h), while docetaxel had three orders of magnitude lower IC50 values: 0.028 µM (48 h) and 0.015 µM (72 h). Combining PYNos (25 µM) and docetaxel (0.01 µM) reduced proliferation by 50% at both time points. Isobologram analysis confirmed strong antiproliferative synergy (sum FIC <1) at 48 and 72 h. Our comprehensive evaluation encompassing apoptosis and cell cycle arrest patterns further validated the synergistic advantages of this combination. In a xenograft mice model using MCF-7 cells, the PYNos-docetaxel co-treatment resulted in significant tumor regression, showcasing promising induction of apoptosis while mitigating docetaxel-associated toxicity. In summary, our findings underscore the substantial microtubule interactions facilitated by 9-3-Pyridyl noscapine, revealing its synergistic potential with docetaxel and establishing a solid foundation for advancing cancer therapeutic strategies. Communicated by Ramaswamy H. Sarma

Synthesis, molecular modeling Insights, and anticancer assessment of novel polyfunctionalized Pyridine congeners

The present study describes synthesizing a novel series of polyfunctionalized pyridine congeners 1–18 and assessed for cytotoxic efficacies versus HCT-116, MCF-7, and HepG-2 among one non-cancerous BJ-1 human normal cell. Most compounds were precisely potent anticancer candidate drugs. The molecular impact of the most active compounds 9, 10, 11, 13, 15, and 17 was evaluated after MCF-7 treatment. The gene expression of pro- and ant-apoptosis markers P53, Bax, Caspase-3 and Bcl-2 as well as VEGFR-2 and HER2 were determined. Compounds 13 and 15 induced upregulation of pro-apoptosis of P53, Bax, Caspase-3 and downregulation of anti-apoptosis Bcl-2 gene. However, compound 15 showed higher effect compared to 13 and respective control. Moreover, a slight reduction in HER2 gene expression was detected due to compound 15 treatment, while VEGFR-2 gene was upregulated. In agreement, the immunoblotting analysis showed higher accumulation of P53, Bax, Caspase-3 proteins and of decrease the Bcl-2 protein levels. Furthermore, docking studies united with molecular dynamic simulation exposed compounds 13 and 15 fitting in the middle of the active site at the interface linking the ATP binding site and the allosteric hydrophobic binding pocket. Finally, we performed Petra/Osiris/ Molinspiration (POM) analysis for the newly synthesized compounds. The evaluation of primary in silico parameters revealed significant differences among individual polyfunctionalized pyridine compounds, highlighting the most promising candidates. These preliminary results may help in coordinating and initiating other research projects focused on polyfunctionalized pyridine compounds, especially those with predicted bioactivity, low toxicity, optimal ADME parameters, and promising perspectives.

Topoisomeric Membrane-Active Peptides: A Review of the Last Two Decades.

In recent decades, bioactive peptides have been gaining recognition in various biomedical areas, such as intracellular drug delivery (cell-penetrating peptides, CPPs) or anti-infective action (antimicrobial peptides, AMPs), closely associated to their distinct mode of interaction with biological membranes. Exploiting the interaction of membrane-active peptides with diverse targets (healthy, tumoral, bacterial or parasitic cell membranes) is opening encouraging prospects for peptides in therapeutics. However, ordinary peptides formed by L-amino acids are easily decomposed by proteases in biological fluids. One way to sidestep this limitation is to use topoisomers, namely versions of the peptide made up of D-amino acids in either canonic (enantio) or inverted (retroenantio) sequence. Rearranging peptide sequences in this fashion provides a certain degree of native structure mimicry that, in appropriate contexts, may deliver desirable biological activity while avoiding protease degradation. In this review, we will focus on recent accounts of membrane-active topoisomeric peptides with therapeutic applications as CPP drug delivery vectors, or as antimicrobial and anticancer candidates. We will also discuss the most common modes of interaction of these peptides with their membrane targets.

Silver nanoparticles formulation of Marrubium alysson L. phenolic extract potentiates cytotoxicity through apoptosis with molecular docking study as Bcl-2 inhibitors

Crude or semi-purified extracts of plants can play a significant role as antitumor agents. They were used as stabilizing and reducing agents in the preparation of silver nanoparticles (AgNPs) that allows these particles to have more efficient cytotoxic activity. In the current study, the extract of Marrubium alysson L., a plant of common occurrence in Egypt was used to synthesize AgNPs for the first time, where comparison of anticancer activity of crude and phenolic extracts with the AgNPs were extensively studied against cancer cell lines PC-3 and HCT-116. Interestingly, AgNPs of the crude extract exhibited promising cytotoxicity with IC50 values of 10.4 and 16.3 μg/ml, while AgNPs of the phenolic extract exhibited very potent cytotoxicity with IC50 values of 2.66 and 1.34 μg/ml compared to Doxorubicin (as a standard reference drug) that exhibited IC50 values of 5.13 and 4.36 μg/ml, respectively against the tested cells. Additionally, AgNPs of the phenolic extract induced apoptosis in HCT-116 with a higher ratio than in PC-3 cells. It induced apoptosis in PC-3 cells by 79.3-fold change, while it induced total colon apoptotic cell death by 228.3-fold change compared to untreated control. Finally, the apoptotic activity of AgNPs of the phenolic extract in the treated PC-3 and HCT-116 cells was confirmed using RT-PCR. As a result, AgNPs of the phenolic extract could be considered a promising anticancer candidate through apoptosis-induction. Communicated by Ramaswamy H. Sarma

Mangrove-Derived Fungi as a Reservoir of Bioactive Secondary Metabolites Promising for Anticancer Leads: A Literature Review

Cancer was the leading cause of death, which accounting for nearly 10 million deaths globally in 2020. Currently, cancer treatment still relies on chemotherapy, however, most anticancer drugs showed non-specific toxicity to normal cell proliferation resulting in various side effects, and are ineffective against many forms of cancer. In addition, the increasing case of chemoresistance of cancer cells to chemotherapy has boosted the discovery of new anticancer agents. Natural products are known as the origin of several clinically used anticancer agents, e.g. taxol and vincristine. Among natural products, mangrove-derived fungi are of particular scientific interest evidenced by the increasing rate of publications on cytotoxic secondary metabolites reported. Hence, this literature review aims to provide comprehensive information on cytotoxic secondary metabolites isolated from mangrove-derived fungi, which might contribute to the search for anticancer leads from natural resources. Data were collected from original research articles published on scientific-based sources such as Google Scholar, PubMed, Taylor and Francis, Elsevier, and MDPI, in the range of 2011-2022. Fifty-four cytotoxic secondary metabolites with IC50 values below 10 µM were described herein, which were classified in to 8 groups of metabolites. These compounds were reported from 16 genera of mangrove-associated fungi. Among them, Aspergillus and Penicillium were the most frequent producers of cytotoxic metabolites, suggesting their enormous potential as a source of pharmacophores for anticancer candidates.

Assessment of the safety of Levilactobacillus brevis CNCM I-5321, a probiotic candidate strain isolated from pulque with anti-proliferative activities.

Gut dysbiosis has been strongly correlated with colorectal cancer (CRC) development and the use of probiotics to modulate this imbalance represents a potential and promising therapy to prevent and treat CRC. For this reason, the identification of novel probiotic strains from diverse origins has widely increased in recent years, including traditional fermented foods. In this work we describe a new strain previously isolated from pulque (a traditional Mexican beverage), Levilactobacillus brevis CNCM I-5321, which may represent an interesting probiotic candidate to prevent and treat cancer. Indeed, our results show that CNCM I-5321 displays significant and specific antiproliferative capacities in human intestinal cancer cell lines (HT-29, HTC-116 and Caco-2 cells), but not in normal cells (FH cells). In addition, CNCM I-5321 is able to induce: (1) a pro-inflammatory immune response through stimulation of interleukin (IL)-2, IL-6, IL-12 and IL-17 cytokines and (2) apoptosis via activation of caspase 8. On the other hand, a minimum inhibitory concentration (MIC) assay revealed phenotypic resistance of this strain to ampicillin and chloramphenicol. However, no known transferable determinants were found in the genome of CNCM I-5321, thus this probiotic candidate presents no risk of horizontal transfer to the intestinal bacterial population. Finally, the safety status of CNCM I-5321 was evaluated using an innovative model of chicken embryo chorioallantoic membrane (CAM) to assess undesirable and/or toxic effects. Overall, our results support that CNCM I-5321 strain is non-pathogenic and safe for potential use as an anti-cancer candidate in human and animal medicine.

A Designed Analog of an Antimicrobial Peptide, Crabrolin, Exhibits Enhanced Anti-Proliferative and In Vivo Antimicrobial Activity.

Antimicrobial peptides have gradually attracted interest as promising alternatives to conventional agents to control the worldwide health threats posed by antibiotic resistance and cancer. Crabrolin is a tridecapeptide extracted from the venom of the European hornet (Vespa crabro). Its antibacterial and anticancer potentials have been underrated compared to other peptides discovered from natural resources. Herein, a series of analogs were designed based on the template sequence of crabrolin to study its structure-activity relationship and enhance the drug's potential by changing the number, type, and distribution of charged residues. The cationicity-enhanced derivatives were shown to have improved antibacterial and anticancer activities with a lower toxicity. Notably, the double-arginine-modified product, crabrolin-TR, possessed a potent capacity against Pseudomonas aeruginosa (minimum inhibitory concentration (MIC) = 4 μM), which was around thirty times stronger than the parent peptide (MIC = 128 μM). Furthermore, crabrolin-TR showed an in vivo treatment efficacy in a Klebsiella-pneumoniae-infected waxworm model and was non-toxic under its maximum MBC value (MIC = 8 μM), indicating its therapeutic potency and better selectivity. Overall, we rationally designed functional peptides by progressively increasing the number and distribution of charged residues, demonstrating new insights for developing therapeutic molecules from natural resources with enhanced properties, and proposed crabrolin-TR as an appealing antibacterial and anticancer agent candidate for development.

Studies on the binding of curcumin and glycyrrhetinic acid to human serum albumin by multi-spectroscopic methods and molecular docking approaches

Human serum albumin (HSA) is the most prevalent and important carrier in plasma, and its interaction with drugs may have a significant effect on the efficacy of drugs. Curcumin (CU) and glycyrrhizic acid (GA) are excellent potential anti-cancer candidates, and studies have shown that the combined application of them can significantly enhance the anti-cancer effect. In order to investigate the interaction of binary systems (HSA-CU/GA) and ternary systems (HSA-CU-GA), we employed spectroscopic methods to study the interaction mechanism and binding affinity, and carried out molecular docking with docking tools. The fluorescence quenching spectrum showed that CU and GA all had fluorescence quenching effects on HSA, and the quenching mechanism were static quenching. The binding sites of CU and GA to HSA were both in site I, and the main force were van der Waals forces and hydrogen bonds. The presence of GA enhanced the affinity between CU and HSA, increased the bioavailability of CU and its stability in plasma. The circular dichroism (CD) and three-dimensional fluorescence experiments showed that CU and GA dramatically altered the conformation of HSA, and GA could enhance the influence of CU on the conformation of HSA. This study aimed at exploring the binding properties of CU/GA to HSA, and providing important theoretical support for their combined use.