Anticancer Research Articles

Polyallylamine antiviral activity against influenza and acute respiratory viral infection in various cell cultures

Acute respiratory viral infections, including influenza, comprise the most common group of seasonal viral infections. Influenza is the most common and dangerous viral infection. The only way to control it is influenza vaccination. Regarding infections caused by parainfluenza and respiratory syncytial virus, only symptomatic treatment is available. Influenza virus quickly bypasses post-vaccination immunity due to its ability to antigenic drift and genetic reassortment. Available antiviral drugs quickly lose effectiveness, especially in relation to highly contagious influenza virus strains. The aim of the study was to create chemotherapeutic agent with a multi-layered effect on all viral structures: surface proteins, lipid membrane and ribonucleoprotein. Such drugs include polyelectrolytes (PE), particularly, polyallylamine (PAA), which showed strong virus-inhibiting effect in combination with low cytotoxicity against several influenza strains in MDCK cell culture and as well as measles virus in Vero cell culture. Materials and methods. In this work, an extended study on PAA antiviral activity and cytotoxicity was carried out using three influenza virus strains in A549 cell line, parainfluenza virus type 3 (HPIV-3) and respiratory syncytial virus (RSV) in A549, HEp-2, Vero, L-41, MA-104 cell lines. Results. It was shown that influenza and RSV were the most sensitive to PAA,so that virus activity decreased by 3 orders of magnitude in human lung carcinoma cells A549. The lowest antiviral activity was registered in Vero cells, which may be because it lacks interferon production system. Based on the results of in vitro experiments, PAA can be considered as a broad-spectrum antiviral drug not only against influenza, but also other human respiratory viruses.

Newly synthesized chitosan nanoparticles loaded with caffeine/moringa leaf extracts Halt Her2, BRCA1, and BRCA2 expressions

Breast cancer is among the highest morbidity and mortality rates in women around the world. In the present investigation we aimed to synthesis novel nanosystem combining two naturally important anticancer agents with different mechanism of action namely Moringa oleifera and caffeine. Firstly, chemical analysis of Moringa oleifera extract and caffeine was done by gas chromatography-mass spectroscopy (GC–MS) in order to assess the main chemical compounds present and correlate between them and the possible anticancer effect. The novel nanosystem was characterized through dynamic light scattering techniques which revealed the stability and homogeneity of the prepared M. oleifera leaves extract/Caffeine loaded chitosan nanoparticles, while FTIR and transmission electron microscope (TEM) proved the shape and the successful incorporation of M. oleifera leaves extract/Caffeine onto the nanochitosan carrier. Our initial step was to assess the anticancer effect in vitro in cancer cell line MCF-7 which proved the significant enhanced effect of M. oleifera leaves extract/Caffeine nanosystem compared to M. oleifera leaves extract or caffeine loaded nanoparticles. Further studies were conducted in vivo namely tumor biomarkers, tumor volume, bioluminescence imaging, molecular and histopathological investigations. The present study proved the potent anticancer effect of the synthesized M. oleifera leaves extract/Caffeine loaded chitosan nanoparticles. Mo/Caf/CsNPs exhibited a large number of apoptotic cells within the tumor mass while the adipose tissue regeneration was higher compared to the positive control. The prepared nanoparticles downregulated the expression of Her2, BRCA1 and BRCA2 while mTOR expression was upregulated. The aforementioned data demonstrated the successful synergistic impact of Moringa and caffeine in decreasing the carcinoma grade.

Approaches based on natural products and miRNAs in pituitary adenomas: unveiling therapeutic intervention.

Pituitary adenomas (PAs) are tumors originating in the pituitary gland, a small gland located at the base of the brain. They are the most common type of pituitary tumor, affecting approximately 1 in 10 people over their lifetime. Common symptoms include headaches, vision problems, hormonal imbalances, and weight changes. Treatment options depend on the type and size of the adenoma and may consist of medication, surgery, radiation therapy, or a combination. PAs are typically benign and slow-growing, but they can cause significant health issues if left untreated. Proper diagnosis and management by an experienced multidisciplinary team is important for achieving the best outcomes. Natural compounds like celastrol, curcumin, quercetin, apigenin, resveratrol, epigallocatechin gallate (EGCG), and genistein have shown the ability to inhibit cell growth, promote cell death, and suppress hormone activity in pituitary tumor cells, suggesting their potential as alternative or complementary treatments for PAs. MicroRNAs (miRNAs) are a kind of tiny RNA molecules that do not code for proteins and have a vital function in controlling gene expression. These 21-23 nucleotide-long molecules regulate gene expression by binding to complementary sequences in mRNA molecules, leading to mRNA degradation. miRNAs participate in a wide range of biological activities, including apoptosis, metastasis, differentiation, and proliferation. The research indicates that miRNAs play a crucial role in the pathogenesis, therapeutic approaches, diagnosis, and prognosis of PAs. This review article will provide a comprehensive analysis of the current understanding of the efficacy of naturally derived anti-cancer agents in the treatment of PAs. Furthermore, the study provides a comprehensive assessment of the miRNAs in PAs, their role in the development of PAs, and their potential application in the treatment of the condition.

Heteronuclear Complexes with Promising Anticancer Activity against Colon Cancer.

This study investigates the activity of novel gold(I) and copper(I)/zinc(II) heteronuclear complexes against colon cancer. The synthesised heteronuclear Au(I)-Cu(I) and Au(I)-Zn(II) complexes were characterised and evaluated for their anticancer activity using human colon cancer cell lines (Caco-2). The complexes exhibited potent cytotoxicity, with IC50 values in the low micromolar range, and effectively induced apoptosis in cancer cells. In the case of complex [Cu{Au(Spy)(PTA)}2]PF6 (2), its cytotoxicity is ×10 higher than its mononuclear precursor, while showing low cytotoxicity towards differentiated healthy cells. Mechanistic studies revealed that complex 2 inhibits the activity of thioredoxin reductase, a key enzyme involved in redox regulation, leading to an increase in reactive oxygen species (ROS) levels and oxidative stress, in addition to an alteration in DNA's tertiary structure. Furthermore, the complexes demonstrated a strong binding affinity to bovine serum albumin (BSA), suggesting the potential for effective drug delivery and bioavailability. Collectively, these findings highlight the potential of the investigated heteronuclear Au(I)-Cu(I) and Au(I)-Zn(II) complexes as promising anticancer agents, particularly against colon cancer, through their ability to disrupt redox homeostasis and induce oxidative stress-mediated cell death.

Environment-responsive dopamine nanoplatform for tumor synergistic therapy

Nanoparticle-based photothermal therapy (PTT) has emerged as a promising approach in tumor treatment due to its high selectivity and low invasiveness. However, the penetration of near-infrared light (NIR) is limited, leading it fails to induce damage to the deep-seated tumor cells within the tumor tissue. Additionally, inefficient uptake of photothermal nanoparticles by tumor cells results in suboptimal outcomes for PTT. In this study, we utilized the adhesive properties of photothermal material, polydopamine (PDA), which can successfully load the photosensitizer indocyanine green (ICG) and chemotherapeutic drug doxorubicin (DOX) to achieve photothermal and chemotherapy synergy treatment (PDA/DOX&ICG), aiming to compensate the defects of single tumor treatment. To extending the blood circulation time of PDA/DOX&ICG nanoparticles, evading clearance by the body immune system and achieving targeted delivery to tumor tissues, a protective envelopment was created using erythrocyte membranes modified with folate acid (FA-EM). After reaching the tumor tissue, the obtained FA-EM@PDA/DOX&ICG nanoparticles can specific bind with folate acid receptors on the surface of tumor cells, which can improve the uptake behavior of FA-EM@PDA/DOX&ICG nanoparticles by tumor cells, and leading to the release of loaded DOX and ICG in response to the unique tumor microenvironment. ICG, as a typical photosensitizer, significantly enhances the photothermal conversion performance of FA-EM@PDA/DOX&ICG nanoparticles, thus inducing tumor cells damage. In vitro and in vivo experimental results demonstrated that the coordinated NIR treatment with FA-EM@PDA/DOX&ICG not only effectively inhibits tumor growth, but also exhibits superior biocompatibility, effectively mitigating DOX-induced tissue damage.

Novel Antimitotic Agent SP-1-39 Inhibits Head and Neck Squamous Cell Carcinoma.

Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC50 values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment.

Reducing Cancer Drug Cost: 3-Year Analysis of Automated Dose Rounding in Electronic Health Records.

Globally, cancer drug expenditure exceeds $185 in US dollars (USD) billion, with the United States contributing $75 (USD) billion. Many cancer drug doses are calculated on the basis of body weight or body surface area, which often results in leftover drug in partially used single-dose vials (SDVs). The cost of wasted drug is a huge financial burden on the US health care system. We evaluated the cost savings resulting from the reduction of SDV wastage, achieved through the implementation of automated dose rounding rules in electronic health records (EHRs). Mayo Clinic implemented automated dose rounding rules within the EHR. These rules were designed to round calculated doses to the nearest SDV if the vial size closely matched the original calculated dose, within a 10% threshold. We assessed doses administered between January 2019 and December 2021, and computed cost-savings, waste reduction, and cost of waste for chemotherapy drugs. In 3 years, 36.1% of doses were rounded down, 35.8% were rounded up, and 28.1% were exact doses. By rounding doses down to a vial size, we achieved cost-savings of $39.75 (USD) million and prevented 62,065 SDV of cancer drugs from going to waste. By rounding doses up, we avoided wasting $9.95 (USD) million worth of drugs. However, there were still instances where the rounding fell outside of the 10%, resulting in wasted drugs worth $25 (USD) million. The substantial burden imposed on patients and the US health care system because of cancer drug wastage is of significant concern. Although the automated dose rounding system represents a partial solution for this issue, a comprehensive approach involves the imperative development of policy and legislative solutions to effectively mitigate the challenges associated with cancer drug waste.

Patients as an additional safety barrier when administering chemotherapeutic agents

Chemotherapeutic agents are high-risk drugs with a high potential for error and serious harm. International studies show that 5-15% of all chemotherapy patients are affected by medication errors. 60% of these errors had the potential to cause harm to patients, 13% resulted in harm and 1% of patients were seriously harmed1. The most common medication errors in the administration of chemotherapy drugs are administration errors and can therefore be observed by the patients themselves. Chemotherapy patients in particular, who often experience the same treatment steps due to their longer treatment duration, often recognise deviations from the usual routine and notice when something is different than usual. They have time to look at the identifying features of chemotherapy and recognise mistakes. In the best case scenario, they communicate these observations, changes or uncertainties to the healthcare professional in charge. In this way, the active involvement of patients provides an additional safety barrier that can be used to support the medical staff. With this in mind, the Quality Management and Clinical Risk Management department has initiated a project together with the Department of Internal Medicine (tumour research), the oncological care experts at Essen University Hospital, the patient networking and self-help officer and other important interfaces such as the LVR Clinic to make the administration of chemotherapeutic agents even safer and to actively involve patients in their treatment.

On the Anticancer Drug Structures and Their Locating Numbers

Cancer is the fast proliferation of unwanted cells in the body. Carcinogens are chemicals that can cause cancer. A carcinogen is a kind of chemical compound found in cigarette smoke. It has the ability to spread to many places in the body. Some of the signs and symptoms of this sickness include a lump, irregular bleeding, a chronic cough, weight gain or loss, and so on. Tobacco chewing is a major factor in this deadly disease. Obesity, a poor diet, laziness, and increased alcohol usage are all factors. Anticancer drugs are being utilized to treat this condition. In this work, we studied some anticancer medicines in terms of locating set, where locating set is a set to settle the entire atom set of a graph into a unique way to access each atom independently. By locating numbers, a particular resolving set is chosen and this resolving set or locating set creates the entire structure into a unique form this helps to study the chemical structure in more depth and detail. So, we can say that locating number helps to understand the chemical structure in more detail and depth. Locating number is a part of resolvability parameters and it also plays a role in developing a unique way to access each node/vertex of a network. When each of its vertices is easily accessible with a unique code, working on a network becomes easy. So this method makes structures of anticancer disease easily understandable and researchers can easily extend working on these structures in medical diagnostics.

The potential cardioprotective effect of Ganoderma lucidum against 5-fluorouracil cardiotoxicity

Background: 5-Fluorouracil (5-FU) is one of the commonly used anti-cancer drugs. However, it ranks as the second most common drug that causes cardiotoxicity. Ganoderma lucidum (G.L.) is a mushroom used for centuries for its different therapeutic properties. The aim of the study is to investigate the potential cardioprotective effect of G.L. against 5-FU cardiotoxicity, anti-inflammatory, and antioxidant properties. Material and methods: Thirty male Albino rats were divided into five groups. The control group was given normal saline orally for 14 days. The second group was treated as the control for 13 days and then 100 mg/kg 5-FU was administered intraperitoneally on day 14. The third group received G.L. 100 mg/kg orally for 13 days followed by a single 100 mg/kg 5-FU intraperitoneally on day 14. The fourth group was treated with 2 mg/kg enalapril orally for 13 days followed by a single 100 mg/kg 5-FU intraperi¬toneally on day 14. The last group received G.L. 100 mg/kg orally for 14 days. On day 15 the animals were eu¬thanized, and blood was collected for biochemical analysis of cardiac biomarkers (troponin (TNNI3) and heart-type fatty acid binding protein (H-FABP)), oxidative stress markers (total antioxidant capacity (TAC) and malondialdehyde (MDA)), and the pro-inflammatory marker (tumor necrosis factor-alpha (TNF-alpha)). The heart tissue was isolated for the histopathological investigation of cyclooxygenase-2 (COX-2) expression. Results: 5-FU administration has led to an increase in the level of H-FABP, TNNI3, MDA, TNF-alpha, and COX-2 expression while it has significantly reduced the level of TAC. G.L. could prevent the 5-FU-induced cardiotoxicity via its effect on all the measured parameters. Conclusion: G.L. can potentially offers cardioprotection against 5-FU-induced cardiotoxi¬city through its antioxidant and anti-inflammatory effects.

Precision-engineered PEGylated liposome for dual payload delivery: enhancing efficacy of Doxorubicin hydrochloride and miR-145 mimics in breast cancer cells

Micro-145 down-regulation is frequently found in breast cancers, indicating its potential as a therapeutic target. The introduction of exogenous miR-145 directly to the tumor sites has been a hurdle due to limited delivery, low bioavailability, and hence lower therapeutic efficacy. Thus, this study aims to synthesize and characterize PEGylated liposome co-loaded with Dox-HCl and miR-145 mimics to investigate its in-vitro anti-proliferative activity against MDA-MB-231 cells. The formulations were developed using a composite central design to optimize nanoparticle size and encapsulation efficiency (EE%) of Dox-HCl and miR-145 mimics. The optimized formulation exhibited the highest desirability function (D = 0.814) and displayed excellent stability over 60 days at 4 °C, maintaining a stable nanoparticle size and zeta potential, with relative EE% of Dox-HCl and miR-145 mimics on the final incubation day 94.97 ± 0.53% and 51.96 ± 2.67%, respectively. The system displayed a higher rate of drug release within 4 h of incubation at an acidic condition. Additionally, the optimized formulation demonstrated a higher toxicity (IC50 = 0.58 μM) against MDA-MB-231 cells than the free Dox- HCl and miR-145 regimen (IC50 = 1.00 μM). Our findings suggest that PEGylated liposome is tunable for effective concurrent delivery of anticancer drugs and therapeutic miRNAs into tumor cells, necessitating further investigation.

Construction and validation of a prognostic model for overall survival time of patients with ovarian cancer by metabolism-related genes.

Ovarian cancer is a female-specific malignancy with high morbidity and mortality. The metabolic reprogramming of tumor cells is closely related to the biological behavior of tumors. The prognostic signature of the metabolism-related gene (MRGs) was established by LASSO-Cox regression analysis. The prognostic signature of MRGs was also prognosticated in each clinical subgroup. These genes were subjected to functional enrichment analysis and tissue expression exploration. Analysis of the MRG prognostic signature in terms of immune cell infiltration and antitumor drug susceptibility was also performed. A MRG prognostic signature including 21 genes was established and validated. Most of the 21 MRGs were expressed at different levels in ovarian cancer than in normal ovarian tissue. The enrichment analysis suggested that MRGs were involved in lipid metabolism, membrane organization, and molecular binding. The MRG prognostic signature demonstrated the predictive value of overall survival time in various clinical subgroups. The monocyte, NKT, Tgd and Tex cell scores showed differences between the groups with high- and low-risk score. The antineoplastic drug analysis we performed provided information on ovarian cancer drug therapy and drug resistance. In vitro experiments verified that PLCH1 in 21 MRGs can regulate the apoptosis and proliferation of ovarian cancer cells. This metabolism-related prognostic signature was a potential prognostic factor in patients with ovarian cancer, demonstrating high stability and accuracy.

Loading co-amorphous on Metal-Organic Frameworks for gelation elimination and anti-cancer drug delivery enhancement

Troublesome gelation occurring during the dissolution of special co-amorphous (COAM) systems poses a limitation on their further applications. Metal-Organic Frameworks (MOFs) are promising porous materials for nano-scale drug delivery due to their high loading capacity and ability to control drug release. Examples of MOFs as drug carriers with the confinement effect for COAM drugs have never been reported. In this study, to eliminate the gelation of the COAM of an anti-cancer drug gefitinib (GTB) and co-former saccharin (SAC) for enhancing their anti-cancer drug delivery, a Zr-based MOF, nanoUiO-67, was selected as drug carrier. The loading process of GTB-SAC COAM on nanoUiO-67 was revealed via a real-time spinning disk confocal fluorescence microscope. The maintenance of molecular interactions between GTB and SAC in GTB-SAC COAM after loaded on nanoUiO-67 was proven experimentally and computationally, along with the host (nanoUiO-67)-guest (drug) interactions. The combined advantages of porous materials nanoMOFs and GTB-SAC COAM were fully demonstrated in terms of excellent physical stability, desirable drug release, good bio-compatibility and higher cytotoxicity towards HeLa cells. It is expected that this novel strategy could have potential application in gelation elimination and developing multi-component drug-loaded MOFs.

A computational approach for screening of phytochemicals from Oxalis corniculata as promising anti-cancer candidates

Objectives.In silico techniques are a highly efficient, cost-effective, and rapid approach to identify potent herbal lead compounds with therapeutic potential against cancer. Phytochemicals are abundant in plants and may represent a promising cancer prevention and treatment approach. The plant species Oxalis corniculata has long been employed in traditional medicine to treat various diseases. Indeed, previous studies have demonstrated the anti-cancer properties of the crude extract obtained from this plant. However, further research is essential to elucidate precisely the underlying molecular mechanisms responsible for these activities.Methods.The study investigated the potential of bioactive compounds from O. corniculata to bind with different targets of anti-cancer drugs. Employing molecular docking and drug-likeness, 19 bioactive compounds from the plant were tested as potential anti-cancer leads. Compounds that exhibit both favorable drug-likeness and binding energies comparable to those of standard drugs like curcumin, doxorubicin, and paclitaxel were selected for further evaluation of their pharmacokinetic properties.Results and Conclusions.Among the 19 selected phytoconstituents of O. corniculata, compounds 15 and 16 exhibited the most effective binding energy (−8.68, −8.22 and −8.70, −8.22, −8.52 kcal/mol, respectively) with key cancer targets including Programmed death-ligand 1 (PDB: 7bea), B-Raf proto-oncogene, serine/threonine kinase (PDB: 8c7y) and poly (ADP-ribose) polymerase (PDB: 7kk4). Pharmacokinetic and toxicity analysis provided additional insights into the potential of these compounds as anti-cancer drugs. The computational analysis holds promise in accelerating the development of novel drug therapies aimed at treating various cancer types.

Aaptamine: A Versatile Marine Alkaloid for Antioxidant, Antibacterial, and Anticancer Therapeutics

Aaptamine (8,9-dimethoxy-1H-benzo[de][1,6]naphthyridine), an alkaloid obtained from marine sponges of the genus Aaptos (Demospongiae, Suberitida, Suberitidae), has attracted significant attention as a promising scaffold for the development of antioxidant, antibacterial, and anticancer agents. This review offers an extensive overview of updated research on aaptamine, focusing on its multifaceted pharmacological properties. The antioxidant potential of aaptamine reflects its potential ability for use in the DPPH free radical scavenging assay, for suppressing ROS, and subsequently deactivating the MAPK and AP-1 signaling pathway. Moreover, it demonstrates notable antibacterial activity against pathogenic bacteria, including mycobacterial active and dormant states, making it a potential candidate for combating bacterial infections. Additionally, aaptamine shows promising anticancer activity by inhibiting cancer cell proliferation, apoptosis induction, and suppressing tumor growth through various signaling pathways, including the regulation of PTEN/PI3K/Akt and CDK2/4, and the regulation of cyclin D1/E in cell cycle arrest. The unique chemical structure of aaptamine offers opportunities for structural modifications aimed at enhancing its antioxidant, antibacterial, and anticancer activities. The exploration of aaptamine as a scaffold in the development of novel therapeutic agents offers great promise for addressing various challenges associated with oxidative stress, bacterial infections, and cancer. This article underscores the potential of aaptamine as a valuable marine-derived scaffold in the fields of antioxidant, antibacterial, and anticancer therapy.

Occurrence of respiratory and urinary tract infections in patients treated with docetaxel compared with afatinib based on a health insurance claims database in Japan.

The relative occurrence of infection in patients treated with cytotoxic chemotherapeutic drugs and molecularly targeted drugs is unclear. To compare the occurrence of respiratory and urinary tract infections in patients treated for lung cancer with docetaxel versus afatinib and to predict the occurrence of the respiratory and urinary tract infections. Data on patients who received docetaxel or afatinib were obtained from a health insurance claims database. After propensity score matching, the occurrence of respiratory and urinary tract infections in each group was compared. Factors associated with respiratory and urinary tract infections were evaluated using multivariable conditional logistic regression analysis. Each group included 855 patients. The occurrence of respiratory infections was significantly higher in the docetaxel group than in the afatinib group (22.6% [193/855] vs. 13.9% [119/855]; p < 0.01). The occurrence of urinary tract infections did not differ significantly by group. Docetaxel was independently associated with a significantly increased risk of respiratory infections (adjusted odds ratio: 1.68, 95% confidence interval: 1.23-2.29), but not urinary tract infections. Patients with lung cancer treated with docetaxel should be closely monitored for the occurrence of respiratory infection in clinical settings.

Tailored amino acid-derived ionic Liquids: Precision chemotherapy for tumors

A set of fourteen imidazolium ionic liquids, each derived from L-amino acids and featuring distinct hydrophobic and hydrophilic components, were synthesized and physicochemically characterized. Thermal analysis showed transition temperatures remaining below 100 °C, being the rigid solid to elastic solid transition temperatures between −27 °C to + 57 °C. The aggregation studies investigated by fluorescence in water and buffered media showed two critical micellar concentrations (CMC) in aqueous media for compounds 7, 8 and 9, with the formation of well-defined aggregates in the second step. The synthesized ILs were assessed for their effects on two cancer cell lines, namely human lung adenocarcinoma A-549 and colon adenocarcinoma HT-29, under both physiological and acidic pH conditions. Furthermore, the influence of the ILs on embryonic kidney cells (HEK-293) was investigated to assess their effect on non-cancerous cells. This study demonstrates that the manipulation of various design vectors allowed for the precise tuning of the structure of ILs, resulting in IC50 values within the micromolar range. ILs featuring a NC12 alkyl side chain in the amide consistently exhibited low IC50 values and a high degree of selectivity against non-tumoral cells under acidic pH conditions. Subsequent investigations were carried out to gain insights into the cellular-level mechanisms of action. These findings provide strong evidence that by meticulously adjusting the molecular structure of these functionalized ILs, it is possible to design potent and selective chemotherapeutic agents.

GLI1 confers resistance to PARP inhibitors by activating the DNA damage repair pathway.

Identifying the mechanisms of action of anticancer drugs is an important step in the development of new drugs. In this study, we established a comprehensive screening platform consisting of 68 oncogenes (MANO panel), encompassing 243 genetic variants, to identify predictive markers for drug efficacy. Validation was performed using drugs that targeted EGFR, BRAF, and MAP2K1, which confirmed the utility of this functional screening panel. Screening of a BRCA2-knockout DLD1 cell line (DLD1-KO) revealed that cells expressing SMO and GLI1 were resistant to olaparib. Gene set enrichment analysis identified genes associated with DNA damage repair that were enriched in cells overexpressing SMO and GLI1. The expression of genes associated with homologous recombination repair (HR), such as the FANC family and BRCA1/2, was significantly upregulated by GLI1 expression, which is indicative of PARP inhibitor resistance. Although not all representative genes of the nucleotide excision repair (NER) pathway were upregulated, NER activity was enhanced by GLI1. The GLI1 inhibitor was effective against DLD1-KO cells overexpressing GLI1 both in vitro and in vivo. Furthermore, the combination therapy of olaparib and GLI1 inhibitor exhibited a synergistic effect on DLD1-KO, suggesting the possible clinical application of GLI1 inhibitor targeting cancer with defective DNA damage repair. This platform enables the identification of biomarkers associated with drug sensitivity, and is a useful tool for drug development.

Fungal endophytes of Taxus species and regulatory effect of two strains on taxol synthesis

BackgroundTaxol, derived from Taxus trees, is a valuable natural resource for the development of anticancer drugs. Endophytic fungi from Taxus trees are a promising alternative source of Taxol. However, the impact of plant-endophytic microbial interaction on the host’s Taxol biosynthesis is largely unknown.ResultsIn the current study, the diversity of endophytic fungi in three different Taxus species was analyzed using Internal Transcribed Spacer sequencing. A total of 271 Operational Taxonomic Units (OTUs) were identified, grouping into 2 phyla, 8 classes, 16 orders, 19 families, and 19 genera. Alpha and beta diversity analysis indicated significant differences in endophytic fungal communities among the various Taxus trees. At the genus level, Alternaria and Davidiella were predominantly found in T. mairei and T. media, respectively. By utilizing a previously published dataset, a Pearson correlation analysis was conducted to predict the taxol biosynthesis-related fungal genera. Following screening, two isolates of Alternaria (L7 and M14) were obtained. Effect of inoculation with Alternaria isolates on the gene expression and metabolite accumulation of T. mairei was determined by transcriptomic and untargeted metabolomic studies. The co-inoculation assay suggests that the two Alternaria isolates may have a negative regulatory effect on taxol biosynthesis by influencing hormone signaling pathways.ConclusionOur findings will serve as a foundation for advancing the production and utilization of Taxus and will also aid in screening endophytic fungi related to taxol production.

A testis-specific lncRNA functions as a post-transcriptional regulator of MDM2 and stimulates apoptosis of testicular germ cell tumor cells

Germ cells preferentially induce apoptosis in response to DNA damage to avoid genomic mutations. Apoptosis of germ cells is closely related to cancer development and chemotherapy resistance; however, its regulatory mechanism is unclear. Here, we suggest that testis-specific lncRNA LINC03074 is involved in male germ cell apoptosis by regulating the expression of the proto-oncogene MDM2. LINC03074 is highly expressed in the sperm of healthy adult testes and cancer cells of testes with testicular germ cell tumors (TGCTs). LINC03074 binds to MDM2 mRNA via an Alu element, thereby reducing MDM2 protein levels. LINC03074 stimulates STAU1-mediated nuclear export of MDM2 mRNA by increasing STAU1 binding to MDM2 mRNA in the cell nucleus, thereby promoting PKR-mediated translational repression in the cytoplasm. The induction of apoptosis in TGCT cells and their responsiveness to the anticancer drug cisplatin is enhanced by LINC03074. Notably, LINC03074 increased E2F1 expression without increasing p53, the primary target of MDM2, and upregulated the apoptotic gene p73, the target gene of E2F1. LINC03074-mediated regulation of apoptosis contributes to the responsiveness of TGCTs to anticancer drug-induced DNA damage.