Anticancer Research Articles

Flavonoid-metal ion Complexes as Potent Anticancer metallodrugs: A comprehensive Review.

Flavonoids and their analogous are mainly found in pink lady apples, green and black tea (catechins), celery and red peppers, onions, broccoli and spinach, berries, cherries, soybean, citrus fruits, and fungi. The different derivatives of flavonoids belonging to polyphenolic compounds such as 3,4',5,7-Tetrahydroxyflavylium (pelargonidin), 2-(3,4-Dihydroxyphenyl)chromenylium-3,5,7-triol (cyanidin), 3,3',4',5,5',7-Hexahydroxyflavylium (delphinidin), 3,3',4',5,7-Pentahydroxy-5'-methoxyflavylium (petunidin), and 3,4',5,7-Tetrahydroxy-3',5'-dimethoxyflavylium (malvidin) can act as good chelating agents for metal-chelate complex formation. These flavonoid-metal complexes have been reported to have various biomedical and pharmacological activities. Flavonoid-metal ion complexes display a broad spectrum of biological properties such as antioxidant, anti-inflammatory, anti-allergic, antiviral, anticarcinogenic, and cytotoxic activity. The literature survey showed that flavonoid metal complexes have potential therapeutic properties against various cancerous cells. The objective is to gain insight into the current perspective and development of novel anticancer metallodrug drugs. The flavonoid-metal ion complexes can be prepared by reacting flavonoid ligand with appropriate metal salt in aqueous or alcoholic reaction medium under stirring or refluxing conditions. In this review article, the various reported methods for the synthesis of flavonoid-metal complexes have been included. The utility of synthetic methods for flavonoid-metal complexes will support the discovery of novel therapeutic drugs. In this review study, short libraries of flavonoid-metal ion complexes were studied as potential anticancer agents against various human cancer cell lines. The review report reveals that metal ions such as Fe, Co, Ni, Cu, Zn, Rh, Ru, Ga, Ba, Sn etc., when binding to flavonoid ligands, enhance the anticancer activity compared to free ligands. This review study covered some important literature surveys for the last two decades. It has been concluded that flavonoid metal complexes have been associated with a wide range of biological properties that could be noteworthy in the medicinal field. Therefore, to develop a new anticancer drug, it is essential to determine the primordial interaction drug with DNA under physiological or anatomical conditions. The study of numerous flavonoid metal complexes mentioned in this paper could be the future treatment against various cancerous diseases.

Ethnopharmacological Survey of Medicinal Plants Used by Local Herbalists and Traditional Healers for the Treatment of Cancer in Jordan

Background: As many Jordanians include herbs in their treatment, an ethnopharmacological survey was conducted to identify the most prescribed plants for the treatment of cancer by local herbalists and traditional healers in Jordan, aiming to encourage the prescription that is based on scientific evidence, to tackle some important practices in traditional healing, and to provide candidates for the isolation of new anticancer agents. Methods: Thirty-two Jordanian herbalists and traditional healers were interviewed. Both the use value and frequency of citation were implemented as quantitative methods to demonstrate the relative importance of a chosen species for the treatment of cancer. Furthermore, literature was screened for evidences that supported or opposed the use of the plants of interest Results: It was revealed that 31 plants are currently used in Jordan for the treatment of cancer, with Curcuma longa and Ephedra foeminea being the most used ones. Conclusions: It was noticed that the use of many prescribed plants could be rationalised by in vitro and/or in vivo studies. However, more attention should be paid by practitioners to some important aspects, such as the method of use and preparation of plants, their interaction with chemotherapeutic agents and the differences in their efficacy against different cancer types.

Systemic hypertension with VEGFR inhibitor (axitinib) therapy in cancer patients: A meta-analysis and systematic review of randomized controlled trials

Vascular endothelial growth factor receptor inhibitors (VEGFRi), namely axitinib, are commonly used chemotherapeutic agents in patients with cancer; however, this medication has a significant cardiovascular side effect profile, such as high-grade hypertension. We performed this updated meta-analysis of RCTs to compile cardiovascular adverse events, such as all-grade and high-grade (>3) hypertension, the risk for thrombosis (DVT and PE), and peripheral edema. A systematic search was performed on PubMed, Cochrane, and Embase from inception until October 2023 for studies using axitinib to treat various cancers. Trials with patients randomly allocated for VEGFRi drug therapy with axitinib and reported all-grade hypertension as an outcome were included. Statistical analysis was performed using Cochrane Review Manager to calculate pooled proportions of odds ratios (OR) with a 95 % confidence interval (CI) using the random-effects model, Mantel−Haenszel method. A total of 8 RCTs and 2502 patients were included in the review. Compared with the placebo group, the VEGFRi (Axitinib) therapy group was associated with a higher risk of all-grade and high-grade hypertension, hand–foot syndrome, and fatigue. Furthermore, there was no increased risk of thromboembolism (DVT/PE) or hypothyroidism. However, a lower risk of peripheral edema was noted between the two groups. Screening for patients with preexisting hypertension, identifying risk factors for cardiovascular diseases before the initiation of VEGFRi therapy, and careful monitoring of high-risk patients during VEGFRi therapy, as well as prompt treatment with antihypertensive drugs, will help mitigate the adverse effects. Further evaluation using prospective designs is required to study the clinical significance and develop mitigation strategies.

Chemobrain: Insight the possible mechanisms of action induced by chemotherapeutic agents.

Chemobrain: Insight the possible mechanisms of action induced by chemotherapeutic agents.

DFT, Molecular Docking, Bioactivity and ADME Analyses of Vic-dioxim Ligand Containing Hydrazone Group and its Zn(II) Complex.

Cancer is one of the diseases affecting a large population worldwide and resulting in death. Finding new anti-cancer drugs that are target-focused and have low toxicity is of great importance. This study aimed to investigate the effects of vic-dioxime derivatives carrying hydrazone group and its Zn(II) complex on cancer using molecular docking, bioactivity and quantum chemical calculations. Molecular docking studies were performed on epidermal growth factor receptor and vascular endothelial growth factor receptor 2 target proteins. Furthermore, molecular geometry was performed, and the frontier molecular orbitals, Mulliken charges and molecular electron density distribution were evaluated using density functional theory. Also, the bioactivity parameters of the compounds were evaluated, and ADME analysis was performed using web-based tools. Higher binding affinity was observed for Zn(II) complex with target proteins vascular endothelial growth factor receptor 2 and against epidermal growth factor receptor when compared with LH2. Only the Zn(II) complex against the epidermal growth factor receptor had ligand efficiency and fit quality in the valid range. Furthermore, LH2 has the most potent electrophilic ability (acceptor) among other compounds. Moreover, both LH2 and Zn(II) complexes strongly satisfy Lipinski's rule of five. In conclusion, these novel compounds, especially Zn(II) complex, can be new candidates for anticancer drug development studies which are target-focused and have low toxicity.

Curcumin-Enclosed Nanoparticles for Cancer Therapy

Abstract: Cancer is the greatest cause of mortality worldwide, and it is distinguished by the unrestrained proliferation of a group of aberrant cells, the random division of cells, and the invasiveness of genetically organized cells. At present, there are various strategies for curing of cancer-based on the type & severity. In the earlier two decades, curcumin has received huge attention in pharmacological, biological, and nutraceutical research. In addition to triggering apoptosis in cancer cells, curcumin also inhibits cancer cell invasion and proliferation by stifling cellular signaling pathways. The lower water solubility of curcumin decreases the oral bioavailability, absorption into the systemic circulation, and chemical stability and finally bound the activity of curcumin as an anticancer agent. The pharmacology of curcumin, as well as its derivatives with relation to its anticancer potential, primary modes of action, & cellular target, has been summarised in this article along with a list of the numerous curcumin enclosing nanoformulations. Multiple methods of administration have been developed for curcumin to boost its specificity. Encapsulation and other formulation processing techniques have been found to enhance both the solubility and bioavailability of curcumin. The nanoparticles' size, shape, surface characteristics, and targeting ligand are all factors that nanoformulation designers must think about when working to increase the efficacy and cellular targeting of anticancer treatments.

Advances in non-Hydroxamate based Histone Deacetylase Inhibitors as Anticancer Agents

Advances in non-Hydroxamate based Histone Deacetylase Inhibitors as Anticancer Agents

In-vitro Antioxidant, In-vitro and In-silico Ovarian Anticancer Activity (Ovarian Cancer Cells-PA1) and Phytochemical Analysis of Cissus quadrangularis L. Ethanolic Extract.

Cissus quadrangularis is a valuable natural source of traditional medicines. An in vitro investigation was performed to determine whether the ethanolic extract from the whole portions of C. quadrangularis had anticancer and free radical scavenging activities against ovarian cancer cells-PA1. C. quadrangularis is a herb collected from rural areas in Andhra Pradesh, India. C. quadrangularis was air-dried and crushed, and the powder and ethanol (0.5 kg) were used in a Soxhlet device for continuous extraction. Phytochemical analysis of the extracts was performed using a standard procedure. The antioxidant activity of the ethanolic extract of C. quadrangularis was evaluated using DPPH. An in vitro anticancer study used an ethanolic extract against the PA1 cell line. Apoptosis of ovarian cancer cells was studied using DAPI and carboxy-H2DCFDA staining. From LC-MS analysis, quercetin-3-O-alpha-Lrhamnopyranoside and erucic acid were docked with the threonine tyrosine kinase (TTK) enzyme using auto docking. The ethanolic extract of C. quadrangularis demonstrated significant dose-dependent antioxidant activity compared to ascorbic acid. The ethanolic extract of C. quadrangularis was found to have high anticancer activity against ovarian cancer cell lines (PA1), with an IC50 value of 482.057 ± 113.857 μg/ml. DAPI and carboxy-H2DCFDA staining confirmed that C. quadrangularis ethanolic extract induced apoptosis in ovarian cancer cells (p < .001). Molecular docking studies helped identify the binding affinities between the protein and ligand complexes, such as Quercetin-3-O-alpha-Lrhamnopyranoside binding sites of target proteins 5N7V (MET602, GLN672) and erucic acid 5N7V (GLY354). Quercetin-3-O-alpha-L-rhamnopyranoside was reported to bind with 5N7V by hydrogen bonding at MET602 and GLN672 amino acids with 2.02, 2.99 Å bonding length distance and binding affinity of -7.9 kcal/mol. Erucic acid was reported to bind with 5N7V by hydrogen bonding at GLY354 amino acid with 3.18, 2.93 Å bonding length (Å) distance and binding affinity of -4.3 kcal/mol. The current analysis showed that the ethanolic extracts of C. quadrangularis L. exhibited antioxidant and anticancer properties against ovarian PA1 cells. The experimental results confirmed that C. quadrangularis L. is a promising, safe chemotherapeutic plant for ovarian cancer PA1 cells. The docking results demonstrated that Quercetin-3-O-alpha-L-rhamnopyranoside strongly binds threonine tyrosine kinase at the MET602 and GLN672 positions. This study showed that the C. quadrangularis ethanolic extract has Quercetin-3-O-alpha-L-rhamnopyranoside, which can be used as an anticancer agent.

Synergistic Effects of Neratinib in Combination With Palbociclib or Miransertib in Brain Cancer Cells.

Aberrant expression and activation of epidermal growth factor receptor (EGFR) resulted in approval of several forms of EGFR inhibitors in the treatment of patients with a wide range of epithelial cancers. However, no EGFR inhibitor has yet been approved for the treatment of patients with brain cancer, indicating that targeting EGFR alone may not be sufficient in some patients. In this study, we investigated the role of all members of the EGFR family, other growth factor receptors, cell-cycle proteins, and downstream cell signaling pathways (e.g., mitogen-activated protein kinase (MAPK), serine/threonine protein kinase (AKT), signal transducer and activator of transcription (STAT3), Src, Abelson murine leukemia viral oncogene homolog (Abl)) on the growth of a panel of human brain cancer cell lines (HBCCLs). We examined the growth response of HBCCLs to treatment with 17 targeted agents compared to two cytotoxic drugs. Of the targeted agents, the irreversible pan-human epidermal growth factor receptor (HER) inhibitors neratinib and afatinib were more effective than erlotinib and lapatinib at inhibiting the growth of all HBCCLs, and the cyclin-dependent kinase (CDK)1/2/5/9 inhibitor dinaciclib was the most potent targeted agent. We found that treatment with Src/Abl/c-kit inhibitor dasatinib, signal transducer and activator of transcription (STAT3) inhibitor stattic, Abl/platelet-derived growth factor receptor (PDGFR)α/vascular endothelial growth factor (VEGFR)2/fibroblast growth factor receptor (FGFR)1 inhibitor ponatinib, and the tropomyosin receptor kinase (TRK)/ROS proto-oncogene 1 receptor tyrosine kinase (ROS)/anaplastic lymphoma kinase (ALK) inhibitor entrectinib, also inhibited the growth of all HBCCLs. Interestingly, these agents were more effective in inhibiting growth of HBCCLs when proliferating at a slower rate. In addition to inhibiting the proliferation of HBCCLs, treatment with neratinib, dinaciclib, dasatinib, stattic and trametinib inhibited the migration of brain tumor cell line A172. Notably, we found that treatment with neratinib in combination with palbociclib (CDK4/6 inhibitor), or miransertib (AKT1/2/3 inhibitor) resulted in synergistic growth inhibition of all HBCCLs. Our results support that repurposing drugs like neratinib in combination with the palbociclib or miransertib may be of therapeutic potential in brain cancer and warrants further investigations.

Identification of Cancer Stem Cell-related Gene by Single-cell and Machine Learning Predicts Immune Status, Chemotherapy Drug, and Prognosis in Lung Adenocarcinoma.

This study aimed to identify the molecular type and prognostic model of lung adenocarcinoma (LUAD) based on cancer stem cell-related genes. Studies have shown that cancer stem cells (CSC) are involved in the development, recurrence, metastasis, and drug resistance of tumors. The clinical information and RNA-seq of LUAD were obtained from the TCGA database. scRNA dataset GSE131907 and 5 GSE datasets were downloaded from the GEO database. Molecular subtypes were identified by ConsensusClusterPlus. A CSC-related prognostic signature was then constructed via univariate Cox and LASSO Cox-regression analysis. A scRNA-seq GSE131907 dataset was employed to obtain 11 cell clusters, among which, 173 differentially expressed genes in CSC were identified. Moreover, the CSC score and mRNAsi were higher in tumor samples. 18 of 173 genes were survival time-associated genes in both the TCGA-LUDA dataset and the GSE dataset. Next, two molecular subtypes (namely, CSC1 and CSC2) were identified based on 18 survival-related CSC genes with distinct immune profiles and noticeably different prognoses as well as differences in the sensitivity of chemotherapy drugs. 8 genes were used to build a prognostic model in the TCGA-LUAD dataset. High-risk patients faced worse survival than those with a low risk. The robust predictive ability of the risk score was validated by the time-dependent ROC curve revealed as well as the GSE dataset. TIDE analysis showed a higher sensitivity of patients in the low group to immunotherapy. This study has revealed the effect of CSC on the heterogeneity of LUAD, and created an 8 genes prognosis model that can be potentially valuable for predicting the prognosis of LUAD and response to immunotherapy.

A mathematical model to study low-dose metronomic scheduling for chemotherapy

Metronomic chemotherapy refers to the frequent administration of chemotherapeutic agents at a lower dose and presents an attractive alternative to conventional chemotherapy with encouraging response rates. However, the schedule of the therapy, including the dosage of the drug, is usually based on empiricism. The confounding effects of tumor-endothelial-immune interactions during metronomic administration of drugs have not yet been explored in detail, resulting in an incomplete assessment of drug dose and frequency evaluations. The present study aimed to gain a mechanistic understanding of different actions of metronomic chemotherapy using a mathematical model. We have established an analytical condition for determining the dosage and frequency of the drug depending on its clearance rate for complete tumor elimination. The model also brings forward the immune-mediated clearance of the tumor during the metronomic administration of the chemotherapeutic agent. The results from the global sensitivity analysis showed an increase in the sensitivity of drug and immune-mediated killing factors toward the tumor population during metronomic scheduling. Our results emphasize metronomic scheduling over the maximum tolerated dose (MTD) and define a model-based approach for approximating the optimal schedule of drug administration to eliminate tumors while minimizing harm to the immune cells and the patient’s body.

Pleurotus pulmonarius polysaccharides inhibit glioma growth through the Hippo signaling pathway and regulate the structure of gut microbiota

Pleurotus pulmonarius (Fr.) is an edible and medicinal fungus. Here, we isolated polysaccharides from P. pulmonarius and evaluated their physicochemical properties, anti-tumor activity, and gut microbiota regulation. Freeze-dried powder of P. pulmonarius fruiting body polysaccharide (PFP) is a heteropolysaccharide, mainly composed of galactose (295.52 μg/mg). PFP significantly inhibited glioma cell survival in vitro and U251 glioma cell tumor growth in nude mice (inhibition rate, 53.70%). PFP inhibited YAP1 and TAZ protein expression levels, upregulated those of MST1 and LAST1, regulated Hippo signaling, stimulated E-cadherin, and downregulated N-cadherin proteins, inhibiting tumor migration. PFP downregulated Bcl-2 protein expression, upregulated that of Cleaved Caspase 3, and induced tumor cell apoptosis. PFP regulated gut microbiota structure in tumor-bearing nude mice and increased the relative abundance of beneficial bacteria. In summary, PFP is a natural, safe, and non-toxic anti-cancer drug, and a potential probiotic. Our data provide theoretical guidance for the treatment of glioma.

Two-dimensional MXene-based nano-prodrug for synergistic chemo-photothermal therapy on cancer treatment

In cancer treatment, although prodrugs have been developed to overcome obstacles such as undesirable pharmacokinetic performance and serious off-target toxicity of most chemotherapeutics, the combination of prodrugs with nanotechnology could be used to overcome the shortcomings of conventional prodrug strategies and facilitate more efficient drug delivery and accumulation of anticancer prodrugs at specific sites/tissues. Phototherapy is a method that uses near-infrared (NIR) light to achieve local and non-invasive tumor therapy. The combination of chemotherapy and phototherapy has shown many therapeutic advantages, including synergistic therapeutic effects and the reduction of toxic and side effects of drugs through dose reduction. In this work, a hydrazone linkage was reported to conjugate Ti3C2Tx MXene nanosheets with doxorubicin hydrochloride (DOX) and methoxy poly(ethylene glycol) benzaldehyde (mPEG-CHO) through a chemical surface modification to form a two-dimensional (2D) nano-prodrug Ti3C2Tx-DOX/PEG (TDP) for synergistic chemo-photothermal therapy. First, hydrazide functionalized Ti3C2Tx was obtained. Then, the carbonyl group of DOX and the aldehyde group of mPEG-CHO can form a pH-responsive hydrazone bond with hydrazide-functionalized Ti3C2Tx. The high surface area of Ti3C2Tx could overcome the reduced drug loading caused by conjugation. Aqueous stability and biocompatibility were enhanced by the introduction of PEG, making the material capable of prolonged circulation in the body’s bloodstream. By achieving excellent antitumor results with this nano-prodrug, we have added another brick to the edifice of Ti3C2Tx MXene as an anticancer drug carrier, and given new vitality to the study of anticancer prodrugs combined with nanotechnology.

Evaluation of Doxorubicin-loaded Echogenic Macroemulsion for Targeted Drug Delivery.

The latest technology trend in targeted drug delivery highlights stimuliresponsive particles that can release an anticancer drug in a solid tumor by responding to external stimuli. This study aims to design, fabricate, and evaluate an ultrasound-responsive drug delivery vehicle for an ultrasound-mediated drug delivery system. The drug-containing echogenic macroemulsion (eME) was fabricated by an emulsification method using the three phases (aqueous lipid solution as a shell, doxorubicin (DOX) contained oil, and perfluorohexane (PFH) as an ultrasound-responsive agent). The morphological structure of eMEs was investigated using fluorescence microscopy, and the size distribution was analyzed by using DLS. The echogenicity of eME was measured using a contrast-enhanced ultrasound device. The cytotoxicity was evaluated using a breast cancer cell (MDA-MB-231) via an in vitro cell experiment. The obtained eME showed an ideal morphological structure that contained both DOX and PFH in a single particle and indicated a suitable size for enhancing ultrasound response and avoiding complications in the blood vessel. The echogenicity of eME was demonstrated via an in vitro experiment, with results showcasing the potential for targeted drug delivery. Compared to free DOX, enhanced cytotoxicity and improved drug delivery efficiency in a cancer cell were proven by using DOX-loaded eMEs and ultrasound. This study established a platform technology to fabricate the ultrasound-responsive vehicle. The designed drug-loaded eME could be a promising platform with ultrasound technology for targeted drug delivery.

Phytochemical Profiling, Evaluation of Heavy Metal Load, Antioxidant and Antibacterial Activity of Various Medicinal Plants

In Ethiopia, medicinal herbs have played a prominent role in relieving pain and curing various diseases for humans and animals for many years. However, consumers don't know what kinds of phytochemicals are in the plants or the amount of metal they contain. Thus, in this study, polyphenol content, flavonoid content, antioxidant capacities, antibacterial activity and the level of metals in Asparagus africanus root, Ferula communis, Stephania abyssinia, Brucea antidysenterica and Vernonia amygdalina, were analyzed. Identifying the phytochemicals, antioxidant and antibacterial activities, and levels of metals in medicinal plants ensures their safety and efficacy and provides a deeper understanding of the healing properties of plants in areas where modern medicines are not easily accessible. The antioxidant activity was determined by 2,2-diphenyl- 1-picrylhydrazyl (DPPH) radical assay, and the antibacterial activity was evaluated by disc diffusion method. Among the studied plant extracts, Vernonia amygdalina displayed the maximum phenolic content (810 mg GAE/100 g), flavonoid content (515.78 mg QE/100 g), and DPPH radical scavenging activity (14.42 mg AAE/g), whereas the least level of total phenolic (160.82 mg GAE/100 g), total flavonoid (30.65 mg QE/100 g), and DPPH radical scavenging (1.14 mg AAE/g) were recorded in Asparagus africanus. The highest inhibition zone was recorded, with an inhibitory zone of 11 mm for S. aurous and 11 mm for E. coli. The least zone of inhibition was obtained in gram-negative bacteria (K. pneumonia) with a diameter less than 8 mm. Asparagus africanus contained the highest levels of Mn and Fe, while Cu and Zn were found to be the highest in Stephania abyssinia. Cr was only detected in Ferula communis, and Cd was found to be below the detection limit. Due to their better antioxidant and antibacterial properties, the extracts of these plants might be used as a natural starting material in treating cancer and to prepare anti-cancer drugs.

DFT Study of Nanotubes as the Drug Delivery Vehicles for an Anticancer Drug

Abstract: Chemicals and poisons in the body interfere with the cell cycle and inhibit the growth of cancer cells. In this way, the function of chemicals in the body is controlled by taking anti-cancer drugs. Due to the degradability and compatibility of carbon nanotubes and boron nitride with the environment, they can act as suitable drug carriers for the transfer of anticancer drugs and deliver the drugs to the target cells. In the current work, the encapsulation of Formestane (FMS) anticancer drug into the carbon (CNT) and boron nitride (BNNT) (8,8) nanotubes was investigated for the first time using the density functional theory: B3LYP/3-21G* and the natural bond orbital analysis in the gas phase. Using natural bond orbital analysis, the charge transfer between FMS drug and CNT and BNNT nanotubes (8,8)/ FMS (BNNT/FMS) complexes were explored. Based on the results obtained from the calculation of encapsulation energy, it was found that the adsorption process was favorable. The interaction effects of FMS drug and CNT and BNNT (8,8) nanotubes on the natural bond orbital charge, the chemical shift parameters, and electronic properties were also evaluated. This study revealed that CNT and BNNT (8,8) nanotubes can be a suitable carrier for FMS drug delivery. The ultraviolet-visible spectra of the FMS drug, the CNT and BNNT (8,8), and the BNNT/FMS complexes were computed using time-dependent density functional theory (DFT: B3LYP) calculations.

1,3-Diaryl Triazenes Incorporating Disulfonamides Show Both Antiproliferative Activity and Effective Inhibition of Tumor-associated Carbonic Anhydrases IX and XII.

The aim of this study was to synthesize a library of novel di-sulfa drugs containing 1,3- diaryltriazene derivatives TS (1-13) by conjugation of diazonium salts of primary sulfonamides with sulfa drugs to investigate the cytotoxic effect of these new compounds in different cancer types and to determine their inhibitory activity against tumor-associated carbonic anhydrases IX and XII. A carbonic anhydrase inhibitory activity of the obtained compounds was evaluated against four selected human carbonic anhydrase isoforms (hCA I, hCA II, hCA IX and hCA XII) by a stoppedflow CO2 hydrase assay. In addition, in vitro, cytotoxicity studies were applied by using A549 (lung cancer), BEAS-2B (normal lung), MCF-7 (breast cancer), MDA-MB-231 (breast cancer), CRL-4010 (normal breast epithelium), HT-29 (colon cancer), and HCT -116 (colon cancer) cell lines. As a result of the inhibition data, the 4-aminobenzenesulfonamide derivatives were more active than their 3-aminobenzenesulfonamide counterparts. More specifically, compounds TS-1 and TS-2, both of which have primary sulfonamides on both sides of the triazene linker, showed the best inhibitory activity against hCA IX with Ki values of 19.5 and 13.7 nM and also against hCA XII with Ki values of 6.6 and 8.3 nM, respectively. In addition, in vitro cytotoxic activity on the human breast cancer cell line MCF-7 showed that some derivatives of di-sulfa triazenes, such as TS-5 and TS-13, were more active than SLC-0111. With the aim of developing more potent and isoform-selective CA inhibitors, these novel hybrid molecules containing sulfa drugs, triazene linkers, and the classical primary sulfonamide chemotype may be considered an interesting example of effective enzyme inhibitors and important anticancer agents.

Phytol and α-Bisabolol Synergy Induces Autophagy and Apoptosis in A549 Cells and Additional Molecular Insights through Comprehensive Proteome Analysis via Nano LC-MS/MS.

Non-Small Cell Lung Cancer (NSCLC) is a malignancy with a significant prevalence and aggressive nature, posing a considerable challenge in terms of therapeutic interventions. Autophagy and apoptosis, two intricate cellular processes, are integral to NSCLC pathophysiology, each affecting the other through shared signaling pathways. Phytol (Phy) and α -bisabolol (Bis) have shown promise as potential anticancer agents individually, but their combined effects in NSCLC have not been extensively investigated. The present study was to examine the synergistic impact of Phy and Bis on NSCLC cells, particularly in the context of autophagy modulation, and to elucidate the resulting differential protein expression using LCMS/ MS analysis. The A549 cell lines were subjected to the patented effective concentration of Phy and Bis, and subsequently, the viability of the cells was evaluated utilizing the MTT assay. The present study utilized real-time PCR analysis to assess the expression levels of crucial apoptotic genes, specifically Bcl-2, Bax, and Caspase-9, as well as autophagy-related genes, including Beclin-1, SQSTM1, Ulk1, and LC3B. The confirmation of autophagy marker expression (Beclin-1, LC3B) and the autophagy-regulating protein SQSTM1 was achieved through the utilization of Western blot analysis. Differentially expressed proteins were found using LC-MS/MS analysis. The combination of Phy and Bis demonstrated significant inhibition of NSCLC cell growth, indicating their synergistic effect. Real-time PCR analysis revealed a shift towards apoptosis, with downregulation of Bcl-2 and upregulation of Bax and Caspase-9, suggesting a shift towards apoptosis. Genes associated with autophagy regulation, including Beclin-1, SQSTM1 (p62), Ulk1, and LC3B, showed significant upregulation, indicating potential induction of autophagy. Western blot analysis confirmed increased expression of autophagy markers, such as Beclin-1 and LC3B, while the autophagy-regulating protein SQSTM1 exhibited a significant decrease. LC-MS/MS analysis revealed differential expression of 861 proteins, reflecting the modulation of cellular processes. Protein-protein interaction network analysis highlighted key proteins involved in apoptotic and autophagic pathways, including STOML2, YWHAB, POX2, B2M, CDA, CAPN2, TXN, ECHS1, PEBP1, PFN1, CDC42, TUBB1, HSPB1, PXN, FGF2, and BAG3, emphasizing their crucial roles. Additionally, PANTHER pathway analysis uncovered enriched pathways associated with the differentially expressed proteins, revealing their involvement in a diverse range of biological processes, encompassing cell signaling, metabolism, and cellular stress responses. The combined treatment of Phy and Bis exerts a synergistic inhibitory effect on NSCLC cell growth, mediated through the interplay of apoptosis and autophagy. The differential protein expression observed, along with the identified proteins and enriched pathways, provides valuable insights into the underlying molecular mechanisms. These findings offer a foundation for further exploration of the therapeutic potential of Phy and Bis in the management of NSCLC.

MiR-26a is a Key Therapeutic Target with Enormous Potential in the Diagnosis and Prognosis of Human Disease.

MicroRNA-26a (miR-26a) belongs to small non-coding regulatory RNA molecules emerging as fundamental post-transcriptional regulators inhibiting gene expression that plays vital roles in various processes of human diseases such as depression, renal ischemia and reperfusion injury, liver injury and some refractory cancer. In this review, we expound on the results of studies about miR-26a with emphasis on its function in animal models or in vitro cell culture to simulate the most common human disease in the clinic. Furthermore, we also illustrate the underlying mechanisms of miR-26a in strengthening the antitumor activity of antineoplastic drugs. Importantly, dysregulation of miR-26a has been related to many chronic and malignant diseases, especially in neurological disorders in the brain such as depression and neurodegenerative diseases as well as cancers such as papillary thyroid carcinoma, hepatocellular carcinoma and so on. It follows that miR-26a has a strong possibility to be a potential therapeutic target for the treatment of neurological disorders and cancers. Although the research of miRNAs has made great progress in the last few decades, much is yet to be discovered, especially regarding their underlying mechanisms and roles in the complex diseases of humans. Consequently, miR-26a has been analyzed in chronic and malignant diseases, and we discuss the dysregulation of miR-26a and functional roles in the development and pathogenesis of these diseases, which is very helpful for understanding their mechanisms as new biomarkers for diagnosing and curing diseases in the near future.

The antioxidant ergothioneine alleviates cisplatin-induced hearing loss through the Nrf2 pathway.

Cisplatin (CDDP) is a commonly used chemotherapeutic agent for treating head and neck tumors. However, there is high incidence of ototoxicity in patients treated with CDDP, which may be caused by the excessive reactive oxygen species generation (ROS) in the inner ear. Many studies have demonstrated the strong antioxidant effects of ergothioneine (EGT). Therefore, we assumed that EGT could also attenuate CIHL as well. However, the protective effect and mechanism of EGT on CIHL have not been elucidated as so far. In this study, we investigated whether EGT could treat CIHL and the mechanism. In our study, we confirmed the protective effect of EGT on preventing cisplatin induced toxicity both in vitro and in vivo. The auditory brainstem response (ABR) threshold shift in the EGT + CDDP treatment mice was 30 dB less than that in the CDDP treatment mice. EGT suppressed production of ROS and pro-apoptotic proteins both in tissue and cells. By silencing Nrf2, we confirmed that EGT protected against CIHL via the Nrf2 pathway. We also found that SLC22A4 (OCTN1), an important molecule involved in transporting EGT, was expressed in the cochlea. Our results revealed the role of EGT in the prevention of CIHL by activating Nrf2/HO-1/NQO-1 pathway, and broadened a new perspective therapeutic target of EGT. EGT decreased ROS production and promoted the expression of antioxidative enzymes to maintain redox homeostasis in sensory hair cells (HCs). Overall, our results indicated that EGT may serve as a novel treatment drug to attenuate CIHL.