Oncology
BCL6 Inhibitors Exhibit Therapeutic Effects on Breast Cancer Cells through the BCL6-STAT4 Pathway
This study aimed to explore the roles of BCL6 and STAT4 in breast cancer their biological functions and their relationships with the prognosis of patients with breast cancer.
Online databases were used to analyze the expression characteristics of BCL6 and STAT4 in breast cancer as well as the correlation between STAT4 and both the prognosis of breast cancer patients and the biological function of breast cancer cells. BC cell lines such as MCF7 and MDA-436 cells were treated with the BCL6 inhibitor TP-021 and STAT4 and BCL6 mRNA expression levels were detected. Sh-RNAs were used to downregulate STAT4 in MCF7 and MDA-436 cells and their proliferation ability was measured via a CCK-8 assay.
BCL6 expression was detected in BC cell lines and tissues but the expression of STAT4 was downregulated in BC and the expression level of STAT4 was negatively correlated with patient prognosis. Inhibition of BCL6 can increase the STAT4 level in BC cells and inhibit their proliferation ability in vitro. Poor prognosis may be related to the expression of STAT4 and the characteristics of immune cell infiltration in tumor tissues.
BCL6 inhibitors demonstrated therapeutic effects on breast cancer cells through the BCL6-STAT4 pathway.
The Pivotal Role of Irradiation-induced Autophagy Mechanisms in Glioma Therapy
Glioma epitomizes exclusively primary brain cancer of glial cell or neuroepithelial derivation and irradiation (IR) is one of the key and standard treatment modalities for all kinds of gliomas. Patients with glioma often undergo IR such as whole-brain radiotherapy stereotactic radiosurgery as well as intensity modulated radiation therapy. However IR therapy for malignant glioma is still facing severe hindrances because gliomas have high resistance to the IR. Autophagy is a type II programmed cell death which has been implicated in IR to gliomas. Autophagy was able to protect cells under sublethal damage circumstances and it differentially triggered cell death after lethal damage in glioma. Furthermore IR induced cerebral vascular damage was associated with progressive endothelial cells loss. IR triggered the acceleration of autophagic flux in cerebral endothelial cells which was characterized with robust upregulation of autophagy genes. Thus autophagy plays a pivotal role in modulating the sensitivity and resistance of glioma cells to IR therapy. However the exact autophagic mechanisms underlying radiosensitivity and/or radioresistance is still a matter of debate and the development of effective radiosensitizers are lacking. Specific conditions pointing to the capabilities of IR-induced autophagy augmentation or inhibition of IR-induced cell death mostly contribute to radiosensitivity or radioresistance. Thus IR-induced autophagy mechanisms in gliomas therapy are multiplex and they either induce radiosensitivity or inhibit radioresistance leading to potential effective treatment strategies for glioma. The aim of this review is to elucidate the autophagic mechanisms associated with radiosensitivity and/or radioresistance in glioma at the bench level and accordingly highlight the development of potentially effective and efficient radiosensitizers to argument the treatment of glioma.
Advanced Technologies for Cancer Immunotherapy: Focus on Gastrointestinal Cancers
Immunotherapy is becoming an alternative method for gastrointestinal cancers such as colorectal gastric and liver cancers. This field of research focuses on utilizing the immune system to recognize and eliminate cancer cells. One important method is immune checkpoint inhibitors which enable T cells to recognize and attack tumor cells by releasing the immune system's brakes. Chimeric antigen receptor (CAR) T-cell therapy is another approach that modifies a patient's T cells to express receptors specific to tumor-associated antigens. Some cancer vaccines have demonstrated positive results in clinical trials particularly colorectal and gastric cancers. Despite progress challenges exist in immunotherapy for gastrointestinal cancers such as treatment resistance limited biomarkers for patient selection and identifying new targets. In this review different immunotherapy methods for all types of gastrointestinal cancers will be studied and the limitations and benefits of each will be discussed in detail. By delving into the various immunotherapy methods their limitations and benefits this review offers valuable insights that could potentially shape the future of gastrointestinal cancer treatment. It not only sheds light on the promising advancements in immune checkpoint inhibitors CAR T-cell therapy and cancer vaccines but also highlights the existing challenges that demand further research and innovation.
Design and Synthesis of 2-substituted [1,2,4]Triazolo[1,5-a]pyrimidines Tethered with Umbelliferone as Selective Carbonic Anhydrase IX and XII Inhibitors
This study presents the design and synthesis of a new series of human carbonic anhydrase (hCA) inhibitors based on a 5-methyl/phenyl-7-(7’-oxycoumarin)-[124]triazolo[15-a]pyrimidine scaffold.
The chemical structures of novel coumarin-based triazolopyrimidines 3a-u were confirmed after using NMR and MS analyses. Their inhibitory profiles were evaluated against a panel of five hCA isoforms. Molecular docking simulations were conducted to elucidate the binding modes of compounds 3d and 3s with hCA IX and XII isoforms. Selected derivatives 3d and 3g were tested for their antiproliferative effects on the medulloblastoma HD-MB03 and the glioblastoma U87MG cell lines. Additionally compounds 3d and 3g were evaluated alone or in combination with cisplatin (cis-Pt) for their ability to induce apoptosis in HD-MB03 cells.
In vitro kinetic studies demonstrated that all 5-methyl triazolopyrimidine derivatives (3a-r) selectively inhibited the tumor-associated hCA isoforms (hCA IX and XII) with KI values ranging from 0.75 to 10.5 μM while hCA I II IV isoforms were not significantly inhibited (KIs > 100 μM). Compound 3d emerged as the most potent and selective inhibitor with KIs of 0.92 and 0.75 μM for hCA IX and XII respectively. This derivative significantly suppressed cell proliferation in human brain tumor cell lines particularly HD-MB03 when it was studied for its adjuvant effects in combination with cisplatin.
In this study we have identified compound 3d as a selective inhibitor of the isoforms hCA IX and XII showing minimal inhibition over hCA I II and IV isoenzymes (selectivity indices > 100). Its moderate inhibitory effects on hCA IX and XII at submicromolar levels were paralleled by significant antiproliferative activity against HD-MB03 cells. These findings underscore the potential of compound 3d as a promising candidate for further therapeutic development especially in combination with clinically used chemotherapeutic agents.
Clinical Efficacy and Safety of Pembrolizumab Therapy for B-cell Lymphoma: A Systematic Review and Meta-analysis
Certain types of non-Hodgkin lymphoma such as Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) often necessitate multiple treatment approaches. One promising avenue is immune checkpoint inhibition specifically targeting the programmed cell death protein 1 (PD-1). Pembrolizumab an immunotherapy medication acts by inhibiting the PD-1 pathway and has gained approval from the United States Food and Drug Administration (FDA) for treating various cancers including melanoma Hodgkin lymphoma lung cancer and endometrial cancer. This meta-analysis aims to assess the impact of pembrolizumab on patient outcomes and survival in the context of B-cell lymphoma.
This study adhered to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Two independent reviewers conducted a thorough search of electronic databases up to September 28 2023. We included studies that investigated the effects of pembrolizumab treatment on patient outcomes and survival in individuals diagnosed with B-cell lymphoma. All statistical analysis was performed by STATA V.17.
Our meta-analysis encompassed 13 eligible clinical trials involving 426 B-cell lymphoma patients. The study findings revealed a Disease Control Rate (DCR) of 63% Overall Response Rate (ORR) of 42% Complete Response Rate (CRR) of 23% and 1-year Overall Survival Rate (OSR) of 64%. Notably 65% of patients experienced Treatment-Related Adverse Events (TRAEs) of any grade with 39% encountering grade ≥ 3 TRAEs. The most prevalent grade ≥ 3 TRAEs included anemia neutropenia thrombocytopenia and lymphopenia.
The utilization of pembrolizumab both as a monotherapy and in combination with other drugs presented encouraging outcomes in patients with B-cell lymphoma.
Evaluation of the cagA, dupA, sabA, babA, and iceA1 Gene Expressions in H. pylori Strains Isolated from Patients with Gastric Cancer and Peptic Ulcer Disease
Helicobacter pylori (H. pylori) is one of the most common human pathogens affecting almost half of the population of the world. Some specific virulence genes of this bacterium have a significant causal effect on the outcome of gastrointestinal diseases. Therefore the aim of this study was to evaluate the expressions of the cagA dupA sabA babA and iceA1 genes of H. pylori cultured from biopsy specimens of patients with GC and PUD and to compare these expressions with those in NUD patients as the control group.
The patients with gastrointestinal disorders referred to Shahid-Beheshti Hospital in Qom Iran were enrolled in this study. Eleven biopsies per patient were collected and used for culture pathology and rapid urease tests. Based on endoscopic and pathological findings patients were separated into three groups: GC PUD and NUD. Colonies suspected of H. pylori were initially investigated using conventional evaluations and then confirmed by PCR assay. Also the RT-qPCR method was used to evaluate the expression of target genes including cagA dupA sabA babA and iceA1 in isolated strains.
One hundred and seventy-seven patients including 31 GC 55 PUD and 91 NUD were included in this study. Among the enrolled patients 29 patients were positive for H. pylori based on three evaluation methods. The expression of bacterial cagA dupA and babA genes in the GC patients was statistically higher than in the NUD group. The expression of the sabA gene in the strain isolated from the GC group was lower than in the control group. No significant difference was observed between the GC group and the control group regarding the iceA1 gene.
Our finding shows that the expressions of cagA dupA and babA virulence genes in H. pylori strains isolated from gastric biopsies of both GC and PUD patients are significantly higher than the NUD ones. Therefore screening and treating the infection caused by this bacterium and determining the genotype in patients may prevent the progression of the disease.
Identification of Active Phytochemicals to Inhibit Signal Transducer and Activator of Transcription 5A (STAT5A) Dimerization for Prostate Cancer Therapy: An In Silico Approach
The Src Homology 2 (SH2) domain the most conserved region of STAT5a/b (aa 573–712) is crucial for receptor-specific recruitment and STAT5 dimerization making it a therapeutic target in prostate cancer (PCa).
This study explored the SH2 domain of STAT5a and carried out the identification of natural STAT5a inhibitors.
Using template-based homology modeling we constructed the structure of human STAT5a (VP1P) and compared it with its 3D crystal of the STAT5a protein obtained from the RCSB database and the model generated by the AlphaFold database. In this study we carried out molecular docking studies using AutoDock Vina on the top 500 natural compounds identified through a pharmacophore search of the ZINC database using ZINCPharmer. Furthermore the top ten compounds with the highest binding energies were evaluated for their drug-likeness and ADMET properties using SWISS ADME and ProTox-II followed by 100 ns molecular dynamics (MD) simulations using the Desmond module of the Schrodinger suite.
Docking studies revealed Pedunculagin (-10.5 kcal/mol) Folic acid (-10.1 kcal/mol) Chebulinic acid (-10.0 kcal/mol) Chebulagic acid (-9.8 kcal/mol) and Oleandrin (-9.8 kcal/mol) as the top candidates compared to the STAT5 inhibitor (Phase-II Clinical Trial) (-8.5 kcal/mol). ADMET analysis confirmed their safety profiles. MD simulations showed stable protein-ligand complexes with all compounds interacting with the conserved Arg638 residue at the active site similar to the STAT5 inhibitor.
Pedunculagin demonstrated the strongest binding energy and stability making it a promising candidate for further development as a novel lead compound to disrupt STAT5a/b dimerization in PCa therapy.
The Role of Cisplatin Prodrugs Bonded to Polymer Carriers for Nanodrug-targeted Treatment of In situ Hepatocellular Carcinoma
The toxic effects of cisplatin limit its therapeutic efficacy on hepatocellular carcinoma (HCC). Cisplatin(IV) (Pt(IV)) with better stability needs an effective drug delivery strategy. Here we explored the toxic and inhibitory effects and cell Pt contents of monomethoxyl poly(ethylene glycol)-block-poly(e-caprolactone)-block-poly(L-lysine) (MPEG-b-PCL-b-PLL)/Pt(IV) micelles (M(P3)) on HCC and evaluated the therapeutic effect of (M (Pt (IV)) on HCC in vitro and in vivo.
We successfully constructed HCC model in BALB/c mice and prepared M(P3). The H22 and HepG2 cells were incubated with cisplatin M(P3) and cisPt(IV)-(COOH)2 at 2 10 20 50 100 and 250 µM equivalent platinum (Pt) concentrations for 48 h and at 5 µM for 2/6 h. The HCC mice received cisplatin M(P3) and cisPt(IV)-(COOH)2 (5 mg equivalent Pt/kg once a week) for five weeks. The cell activity was assessed by MTT assay. The Pt contents were assayed by an inductively coupled plasma mass spectrometer (ICP-MS). The liver tumor weight was measured. The levels of liver tumor hepatorenal function indicators and malignant indicators were estimated by biochemical analysis and Western blot.
The activity of H22 and HepG2 cells: cisPt(IV)-(COOH)2-treated > M(P3)-treated > cisplatin-treated. The Pt contents of H22 and HepG2 cells: M(P3)-treated > cisplatin-treated > cisPt(IV)-(COOH)2-treated cells. The hepatorenal function of HCC mice: M(P3)-treated > cisPt(IV)-(COOH)2-treated > cisplatin-treated. According to the weight and levels of malignant indicators of liver tumor the therapeutic effect on HCC mice: cisplatin-treated > M(P3)-treated > cisPt(IV)-(COOH)2-treated.
Although the inhibitory effect of M(P3) on HCC is not as good as cisplatin M(P3) has significantly lower hepatorenal toxicity and remarkably higher cell Pt contents.
Recent Approaches on Oncolytic Viruses, Aptamers, TTFields and Personalized Treatment used for the Management of Glioblastoma: A Comprehensive Review
Glioblastoma (GB) remains a formidable challenge in oncology with current treatment approaches providing only marginal improvements in patient outcomes. Despite significant advances in understanding its molecular and genetic characteristics median survival for untreated patients remains distressingly low emphasizing the urgent need for novel therapeutic strategies. This review comprehensively examines the standard first-line treatments for GB including surgery concomitant radio-chemotherapy and maintenance chemotherapy while highlighting the limitations of these approaches. Consequently we explore emerging novel therapeutic modalities such as Oncolytic Viral Therapy with genetically modified oncolytic viruses that enhance the capabilities of antigen-presenting cells. These cells migrate to lymph nodes to recruit cytotoxic CD8+ T lymphocytes directing them to the site of infection where they eradicate cells that promote tumour growth. Aptamer-based therapies such as GMT-3 AS1411 GS24 GMT8 and Gint4.T which exhibit specificity for their biological targets and can act as drug transporters by facilitating receptor-mediated transcytosis within the endothelial cells of the blood-brain barrier thus improving drug delivery. Tumour-treating fields (TTFields) that have shown increased overall survival rates in patients. Personalized genomic medicine driven by biomarkers which provokes immune responses tailored to the tumour’s specific antigens thereby customizing patient-specific treatments to improve effectiveness. By synthesizing current evidence and recent breakthroughs we underscore the potential use of advancing novel therapies to address the unmet clinical needs of GB patients and ultimately enhance their overall survival and quality of life.
Maternal Embryonic Leucine Zipper Kinase (MELK) as a Promising Therapeutic Target in Triple Negative Breast Cancer
Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine protein kinase involved in regulating key cellular processes including cell cycle progression apoptosis embryonic development spliceosome assembly and gene expression. Notably MELK is overexpressed in Triple-Negative Breast Cancer (TNBC) an aggressive malignancy associated with poor prognosis high drug resistance and limited treatment options. Given its critical role in TNBC pathogenesis MELK has emerged as a potential biomarker and therapeutic target. This review explores the molecular functions of MELK its involvement in oncogenic signaling pathways and the development of MELK-targeting small-molecule inhibitors.
A comprehensive literature review was conducted to evaluate current knowledge on MELK including its molecular functions interactions within signaling pathways role in TNBC progression and potential as a therapeutic target. Relevant databases including PubMed Web of Science Embase and Scopus were searched for studies related to MELK expression signaling mechanisms and experimental therapeutic approaches.
MELK plays a central role in oncogenic signaling pathways that drive TNBC proliferation and survival. Preclinical studies have demonstrated that MELK inhibition can suppress TNBC cell growth and enhance chemotherapy efficacy. Several small-molecule inhibitors targeting MELK have shown promising anti-tumor activity in preclinical models. However challenges remain in translating these findings into clinical applications due to drug specificity limitations and resistance mechanisms.
MELK is a promising biomarker and therapeutic target in TNBC. However further research is required to refine MELK inhibitors enhance clinical efficacy and overcome drug resistance mechanisms. Targeting MELK could offer a novel therapeutic strategy to improve TNBC treatment outcomes.
Recurrent Missense Driver STAT5B N642H Mutation in Children Transiting into Adolescence, with Acute Lymphoid Leukemia and its In silico Inhibition
The occurrence of gain of function mutations in STAT5B has been associated to survival and drug resistance in Leukemia. In silico screening of compounds having inhibitory potential towards mutated proteins can be helpful in the development of specific inhibitors.
This study was designed to screen selected JAK-STAT mutations in leukemia patients and virtual exploration of molecular interaction of potential inhibitors with their mutated products.
In total 276 patients were randomly recruited for this study. Demographic and clinical data were summarized. The genetic status of JAK1V623A JAK2 S473 and STAT5BN642H were screened through allele specific PCR. In-silico analysis was performed on wild type and mutant protein sequences retrieved from Protein databank. The ligands and protein were prepared through standard protocols and docking was performed through Auto Dock Vina 1.2.0.
Acute lymphoblastic leukemia comprises 70% of the total patients. Male to female ratio was 3:1. All the patients were homozygous for JAK1V623A JAK2 S473 major allele. However 6 patients (5 male 1 female) with ALL were STAT5BN642H+. The molecular docking of the ligands to wild type and STAT5BN642H+revealed that AC-4-130 Pimozide Indirubin and Stafib-2 have higher but differential docking affinities for SH2-domain of both normal and mutated STAT5B. However AC-4-130 has a higher affinity for wild type and Stafib-2 has stable molecular interaction with STAT5BN642H+.
The aggressive form of pediatric leukemia carrying STAT5BN642H+ mutation is identified in the studied population. It is predicted that AC-14-30 and stafib-2 have potential for inhibition of constitutively active STAT5B if optimized for use in combination therapy.
A Systematic Quantitative Approach to Rational Drug Design and the Discovery of Novel Human Antigen R (HuR) Inhibitors
14-Naphthoquinone and its derivatives are recognized for their potent anticancer effects establishing this pharmacophore as a key focus in cancer research. Their potential to modulate cellular pathways suggests they could be effective in developing new HuR inhibitors targeting a protein crucial for regulating cancer-related gene expression. Compounds C1-C20 were designed by using Discovery Studio (DS) software.
In this study a systematic approach involves scaffold hopping followed by additional research such as molecular docking ADMET drug-likeness toxicity prediction molecular dynamic (MD) simulation and binding free energy analysis was used to discover novel Human Antigen R (HuR) inhibitors.
In molecular docking 14-Naphthoquinone derivatives showed better interactions with the HuR protein compared to that of the conventional HuR inhibitor MS-444. Among twenty 14-Naphthoquinone derivatives most of the compounds showed favorable pharmacokinetic characteristics. In the toxicity prediction model most of the designed compounds were neither mutagenic nor carcinogenic. According to MD simulation C5 is more stable than MS-444.
The designed 14-Naphthoquinone derivatives have been found to be crucial structural motifs for the discovery of novel HuR inhibitors which was well supported by the in-silico screening and molecular modeling methods.
Preliminary Investigations on Acyl Hydrazones Bearing Sulfonamides as Inhibitors of the Human Carbonic Anhydrase Isoforms I, II, IX, and XII
The present study aims to identify the synthesis and structural characterization of acyl hydrazone-sulfonamide-containing compounds that were tested in vitro on human carbonic anhydrase (hCA) isoforms I II IX and XII.
Herein acyl hydrazone derivatives containing the primary sulfonamide moiety were synthesized via a three-step synthetic pathway starting from the commercially available 4-sulfamoyl benzoic acid. Structural characterizations of the final compounds were assessed through IR IR 1H-NMR 13C-NMR and elemental analyses. The in vitro profiling activity of the final compounds on the Carbonic Anhydrases (CAs; EC 4.2.1.1) I II IX and XII were performed by means of the stopped-flow technique and revealed nanomolar inhibitory potencies on the selected targets. Molecular docking and molecular dynamic simulations afforded a detailed understanding of the binding modes of the most effective compounds.
We reported the synthesis and structural characterization of 25 acyl hydrazone-sulfonamide-containing compounds that were tested in vitro on the hCAs I II IX and XII isoforms for their inhibitory features. Overall all compounds showed nanomolar inhibition potencies on the panel of hCAs considered and their binding modes were deciphered by means of in-silico studies. Molecular docking followed by MD simulations confirmed the stability of 4l-hCA I 4n-hCA II 4t-hCA II 4v-hCA XII and 4w-hCA XII complexes.
This study presents a deep understanding of the structural determinants influencing the affinity and selectivity of the designed compounds towards different hCAs thus offering valuable insights for further optimization and development in the field.
Screening of Bioactive Fractions from Balanites aegyptiaca and Pterocarpus marsupium for Anticancer Effects in HepG2 and U87MG Cells
Cancer is a group of diseases caused by uncontrollable cell growth. Herbal medicines derived from plants have been used for centuries across cultures for their therapeutic benefits effectively treating conditions like cancer. This study represents the anticancer effects of fractions of some medicinal plant extracts along with their apoptotic studies and their induction through p53-mediated Bax and Bcl-2 mRNA expression in HepG2 and U87MG cells.
The fractionation of crude methanolic extracts was done using Column Chromatography and Thin Layer Chromatography. The fractions were analysed for cytotoxicity against both the cell lines by MTT assay. Cancer cells were treated with 2 most active fractions and their mechanism of apoptosis induction was assessed by Flow Cytometry studies and the mRNA expression levels of p53 Bax and Bcl-2 were determined by Reverse Transcriptase PCR. The presence of phytoconstituents in the active fractions was analysed by GC-MS.
The active fractions revealed the apoptosis induction in both the cell lines and the RT-PCR studies suggested the mechanism of apoptosis induction through upregulation of p53 and Bax and downregulation of Bcl-2 mRNA. The GC-MS analysis of active fractions from Balanites aegyptiaca and Pterocarpus marsupium revealed the presence of phytochemicals such as 4-O-Methylmannose Oleic acid Erucic acid etc. which might have contributed to the anti-proliferative and apoptotic effects of these fractions.
4-O-Methylmannose was the major component identified with the highest peak area of 59%. The fractions from all the 4 plant extracts demonstrated significant cytotoxic effects on the liver (HepG2) and brain (U87MG) cancer cell lines with particular emphasis on the active fractions BA FII PM FII and PM FIII. Additionally the mechanisms of apoptosis induction through the modulation of p53 Bax and Bcl-2 pathways along with the presence of bioactive compounds further support the anticancer efficacy of these plant extracts. Also to the best of our knowledge this is the first study on fractions of Balanites aegyptiaca and Pterocarpus marsupium against U87MG cells.
The results highlight the promising potential of plant-derived natural products as anticancer agents. These findings provide valuable insight into the potential of herbal medicines and encourage further exploration of plant-based therapies for cancer treatment.
Redefining Anthraquinone-based Anticancer Drug Design through Subtle Chemical Modifications
Anthraquinones are well known for their wide spectrum of pharmacological properties. Anthraquinone antibiotics such as doxorubicin daunorubicin epirubicin and mitoxantrone have long been used in the clinical management of various tumors. However their use is limited due to their toxicity effects especially cardiomyopathy despite their pronounced therapeutic effects. In recent years medicinal chemists have explored the possibility of modifying the anthraquinone ring appended with structurally diverse functionality in order to develop better chemotherapeutic agents with fewer adverse effects. The fused polycyclic structure of anthraquinone offers rigidity planarity and aromaticity which helps in double helix DNA intercalation disruption of G4 DNA and inhibition of topoisomerase-II enzyme of cancer cells making them suitable pharmacophore for anticancer drug discovery. Incorporation of suitable functional groups such as amino hydroxyl and their derivatives into anthraquinone rings can improve their interactions with biological targets involved in cancer progression. These subtle structural changes produce newer anthraquinone derivatives with improved anticancer properties increased potency selectivity and reduced toxicity and can overcome multi-drug resistance. On the other hand the molecular hybrids of the anthraquinone derivatives have been reported to act on multiple targets in cancer cells as seen in the case of clinical candidates like alectinib midostaurin tucatinib belinostat and dacinostat. Molecular hybrid has given a new direction for anticancer drug development which can produce bifunctional drug candidates with reduced toxicity. This review summarizes different structural modifications that have been made to the anthraquinone ring in the last decade with the aim of bringing out potent yet toxicity-free anticancer agents.
A Path to the Formation Mechanism of Propolis Nanoparticles, their Cytotoxicity on 3T3 Fibroblasts, Metastatic Murine B16F10 Cells, and their In vivo Irritability in Animals
Natural products such as propolis are an important source of biologically active compounds with the potential to treat health disorders. Propolis is a well-known waxy resin recognized for its antimicrobial immunomodulatory and cytotoxic effects.
In this study we aimed to clarify the formation mechanism of propolis nanoparticles from the perspective of their stability and chemical composition. By evaluating the light absorption behaviour of the nanoparticles formed in different media and quantifying the polyphenols we show that they are superficially hydrophobic nanoparticles with the capacity to encapsulate some polar compounds.
Biological activity was evaluated by in vitro cell viability performed on NIH/3T3 fibroblasts incubated with 10 100 and 1000 μg/mL of propolis nanoparticles for 48 hours.
The results show that nanoparticles are cytocompatible with a proliferation effect. In contrast the results of the viability of metastatic murine B16F10 cells indicate that a dose with a concentration of 5 µg/mL in the cell culture media is sufficient to stop the abnormal cell growth having an antitumor effect. This effect might be related to the flavonoids present in the propolis nanoparticles. In vivo dermal irritability tests on New Zealand rabbits show that propolis nanoparticles' aqueous dissolution was non-irritant.
According to the results obtained from this study reducing the size of raw propolis down to nanoparticles and dispersing them in water solvents enhance its positive effects. The superficially hydrophobic propolis nanoparticles encapsulate active compounds such as polyphenols and flavonoids which also confirms their ability to generate selective effects on the cells depending on their nature.
Identification of Flavonoid-based Hypoxia-inducible Factor-2 Alpha Inhibitors for the Treatment of Breast Cancer– In silico and In vitro Evidence
Breast cancer (BC) is a common malignancy that poses a serious threat to women's health. The hypoxic tumor microenvironment in BC promotes drug resistance making hypoxia-targeted therapies crucial. Targeting hypoxia-inducible factors (HIFs) particularly HIF-2α has emerged as a promising approach to inhibit tumor growth and improve response to chemotherapy and radiotherapy. However further research is required to fully understand the role of HIF-2α to develop more effective treatments for BC.
The aim of this study is to identify phytochemicals that target HIF-2α and evaluate their effects on the MCF-7 breast cancer cell line under hypoxic conditions.
Molecular docking identified phytochemicals targeting HIF-2α with high-affinity compounds undergoing stability evaluation via GROMACS molecular dynamics simulations. ADMET and toxicity assessments were performed using SwissADME and ProTox-3.0. In vitro assays on hypoxic MCF-7 cells examined cell viability and gene expression. The expression of HIF-2α-regulated genes (VEGFA CCND1 GLUT1) was analyzed by using qRT-PCR.
Molecular docking revealed that naringin (-8.2 Kcal/mol) and morin (-7.1 Kcal/mol) showed better binding affinity than the standard drug belzutifan (-7.7 Kcal/mol). Dynamic simulations including RMSD RMSF H-bond interactions Rg SASA and PE confirmed their strong binding potential. Morin in particular demonstrated more H-bond interactions and met Lipinski's Rule of Five making it a promising candidate for in vitro studies. It reduced cell viability with an IC50 of 118 µM and significantly downregulated HIF-2α-associated genes.
Morin demonstrated promising anti-cancer activity under hypoxic conditions by inhibiting HIF-2α in the hypoxia signaling pathway.
Retraction Notice to "Anti-proliferative, Morphological and Molecular Docking Studies of New Thiophene Derivatives and their Strategy in Ionic Liquids Immobilized Reactions"
Gut Microbiota and the Gut-liver Axis in Hepatocellular Carcinoma: A Comprehensive Review of Pathogenesis and Therapeutic Strategies
Hepatocellular carcinoma (HCC) is among the most prevalent and fatal cancers globally. The gut-liver axis involving intricate interactions between gut microbiota and the liver has emerged as a critical pathway in HCC development. This review comprehensively examines the molecular mechanisms by which gut microbiota contribute to hepatocarcinogenesis. It discusses factors that either protect against or promote HCC such as bacterial translocation and explores the biological processes that drive carcinogenesis while addressing clinical and pathophysiological complexities. Special attention is given to the role of toll-like receptors (TLRs) and inflammation in liver cells where microbial components trigger changes in TLR activation leading to increased inflammation and fibrosis. Additionally the review covers obesity-related HCC highlighting the impact of gut microbiota alterations on this cancer type. It critically assesses current literature on therapeutic interventions targeting gut microbiota in HCC focusing on strategies like probiotics and antibiotics that could modulate microbial composition to prevent HCC progression. The review also explores gut microbiota-derived biomarkers for early detection and monitoring of HCC and discusses personalized therapies based on individual gut-liver interactions. Finally it identifies research gaps and suggests future studies to deepen understanding of how gut microbiota can be leveraged as an adjunct therapy in HCC. Overall the review underscores the pivotal role of gut microbiota in HCC pathogenesis and treatment pointing to microbiome modulation as a promising therapeutic avenue.
Potentials of N-Acyl Hydrazones Against Colorectal Cancer: A Mini Review
Colorectal cancer (CRC) is a malignant gastrointestinal tract disorder with high occurrence and mortality index and showing an upsurge. Standard therapies for treating CRC are surgery and chemotherapy. Despite great effort in developing effective treatments the progress is limited due to its relapse and recurrence. Prognosis of metastatic CRC is always complicated. This condition can be evaded by a novel approach i.e. targeted therapy which increases the survival rate in CRC patients by blocking important pathways and acting on immune checkpoints. Drugs with N-acyl hydrazones (NAH) are currently being employed treatment of infectious diseases and disorders. NAH in combination with diverse heterocycles natural product isolates are identified as interesting CRC inhibitors under-explored. This review provides an overview of the existing CRC targeted compounds having acyl hydrazones hydrazine hydrazides moieties and their underlying mechanisms towards different CRC cell lines together with a discussion of their limitations and future trends.