Cancer Cells Research Articles

Effects of Vitamins E and D on Mechanical Properties of Breast Cancerous Cells

Background: Several investigations have demonstrated that vitamins can treat or prevent cancer by altering actin filaments and inhibiting cell migration and proliferation. Vitamins D and E are fat-soluble. This research aims to determine the short-term impact of vitamin D and E on the mechanical properties of breast cancer cells before comparing them with normal breast cells. Methods: Atomic force microscopy (AFM) was used to examine the deformation of MCF-10 normal breast cells, MCF-7 breast cancer cells, and MCF-7 breast cancer cells treated with 0.03 μM vitamin D and 16 μM vitamin E solutions. Young's modulus was calculated employing the Hertz model to determine cell stiffness. Results: The Young's modulus of vitamin D-treated cancer cells (585.8 Pa) was substantially similar to that of normal cells (455.6 Pa). Nevertheless, vitamin E treatment did not affect Young's modulus of cancer cells, which remained remarkably similar to that of untreated cancer cells (216.6 and 203.4 Pa, respectively). Conclusion: Unlike vitamin E, vitamin D enhances the stiffness of tumor cells and makes their mechanical properties similar to normal cells by interfering with actin filaments and cell skeletons, which may inhibit tumor cell migration. Based on these findings, vitamin D appears to be an effective drug for cancer treatment.

Anticancer activity of synthesized 5-benzyl juglone on selected human cancer cell lines.

Cancer is a malignant disease that causes millions of deaths each year worldwide. As one of the cancer therapeutic strategies, chemotherapy is a means to destroy rapidly dividing cells. The main problem with cancer chemotherapy is the lack of selectivity of conventional chemotherapeutic drugs, leading to toxicity towards normal cells. Therefore, the discovery of anticancer agents with selectivity for fast-growing cancer cells was desirable. In this study, we report the synthesis and identification of the novel 5-benzyl juglone as a potential anticancer agent with selectivity toward certain cancer cell lines. An efficient synthetic method for 5-benzyl juglone has been established. The proliferation of cancer cell lines and a normal cell line treated by the target compound were studied using an MTT assay. In addition, the cell cycle arrest and apoptosis were determined by flow cytometry. Based on the Diels-Alder (D-A) reaction between 3,6-dimethoxy benzyne intermediate with furan, further acid-catalyzed intramolecular rearrangement and CAN-mediated oxidation, a convenient synthesis of 5-benzyl juglone has been achieved with high overall yield. The results from in vitro biological evaluation indicated that the juglone derivative exhibited potent antiproliferative activity against HCT-15 human colorectal cancer cells with an IC50 value of 12.27 μM. It exerted high inhibitory activity toward MCF-7 human breast cancer cells and, to a much lesser extent, to corresponding MCF-10A human breast epithelial normal cells with the IC50 ratio (IC50 in MCF-7 divided by IC50 in MCF-10A) of 0.62. The mechanistic investigations indicated that 5-benzyl juglone could induce cell cycle arrest at the G0/G1 phase and promote apoptosis of HCT-15 cells. The apoptotic effects possibly also contributed to its higher selectivity toward cancer cells than normal cell lines.

Chemical Composition, Antifungal, Antibacterial, Antioxidant, Antiviral and Cytotoxic Activities of Ruta chalepensis L. Fixed Oil from Saudi Arabia

An aromatic plant is called Ruta chalepensis L. known locally as “Fidjel,” grows in rocky, arid places. Its pharmacological activities are pleiotropic. The goal of the present investigation was to use GCMS and HPLC analysis to identify the chemical constituents of oil extracted from Ruta chalepensis L. and assess its antibacterial, antifungal, antioxidant, antiviral, and anticancer properties. Linoleic acid was the most predominant acid found in Ruta chalepensis L. oil, then oleic acid, palmitic acid, and linolenic acid. 13.64 μg/mL of tocopherol (α-, β-, and γ-tocopherol) was identified. The primary phytosterols are β-sitosterol and campesterol. At 200 μL/mL of Ruta chalepensis L. oil, phenolic components rated 84.4 GAE/mL and had 94.0% antioxidant activity. Zone inhibition efficacy of Ruta chalepensis L. oil against microbial strains, particularly E. coli with a diameter of 42.3 mm, was demonstrated. MBC (30 μL/mL and 40 μL/mL) are the bactericidal action against E. coli and S. aureus, while MIC bacteriostatic (30 μL/mL) was also demonstrated. However, Ruta chalepensis L. oil was ineffective against Saccharomyces cervisia and fungal strains. Weak inhibitory impact of Ruta chalepensis L. oil was observed against the PC-3 (prostate cancer) cell line. Nonetheless, it had a significant inhibitory impact on the A2780 (ovarian cancer) cell line. At 100 μg/mL of oil, Ruta chalepensis L. oil showed a low antiviral impact (7.93±2.03%) against the herpes simplex virus type 2 (HSV-2). Oil from Ruta chalepensis L. is a promising option for the medical management of non- transmissible illnesses, since it is wealthy in antioxidants and bioactive substances.

Exploring the Therapeutic Potential of Chalcones in Oncology: A Comprehensive Review

Abstract:: Chalcone is a bioactive flavonoid contained in various plants such as Angelica archangelica, Pueraria lobata, and Glycyrrhiza glabra. It has been studied extensively in the field of pharmaceutical sciences due to its significant role in therapeutic potential including antibacterial, antiinflammatory, analgesic, cytotoxic, and anti-tumour properties. A plenty of study indicated numerous chalcone derivatives exhibit enhanced potency and reduced toxicity as compared to natural analogues. In this review, we introduce chalcone and its various derivatives including 1- naphthylacetophenone, 2-benzimidazolyl, 2-furoyloxy, 3-(furan-2-yl)pyrazol-4-yl, 4'-alkoxy, 4- anilinoquinolinyl, 4-aryloxyquinazolines, acridine, benzamide, benzenesulfonamide, bischalcone, cinnamoylthiazoles, D-glucosyl azides, dialkylamino, dihydropyrimidinone, indole, isoquinoline, ligustrazine, morpholinothiazole, naphthalene, quinoline, sulphonamide, thiazoleimidazopyridine, thienyl, thiophene, triazines, triazole-benzimidazole, tri-methoxyphenyl, and α- trifluoromethyl hybrids and display their promising activity against various cancer cell lines, such as breast cancer, prostate cancer, colon cancer, lung cancer, cervical cancer, and liver cancer.

Synthesis and Anticancer Activity of Novel Indole Derivatives as Dual EGFR/SRC Kinase Inhibitors.

Recent studies showed that the cooperation between c-SRC and EGFR is responsible for more aggressive phenotype in diverse tumors, including glioblastomas and carcinomas of the colon, breast, and lung. Studies show that combination of SRC and EGFR inhibitors can induce apoptosis and delay the acquired resistance to chemotherapy. Therefore, such combination may lead to a new therapeutic strategy for the treatment of EGFR-mutant lung cancer. Osimertinib was developed as a third-generation EGFR-TKI to combat the toxicity of EGFR mutant inhibitors. Due to the resistance and adverse reaction of osimertinib and other kinase inhibitors, 12 novel compounds structurally similar to osimertinib were designed and synthesized. Recent studies showed that the cooperation between c-SRC and EGFR is responsible for more aggressive phenotype in diverse tumors, including glioblastomas and carcinomas of the colon, breast, and lung. Studies show that combination of SRC and EGFR inhibitors can induce apoptosis and delay the acquired resistance to chemotherapy. Therefore, such combination may lead to a new therapeutic strategy for the treatment of EGFR-mutant lung cancer. Osimertinib was developed as a third-generation EGFR-TKI to combat the toxicity of EGFR mutant inhibitors. Due to the resistance and adverse reaction of osimertinib and other kinase inhibitors, 12 novel compounds structurally similar to osimertinib were designed and synthesized. Compounds were synthesized by developing novel original synthesis methods and receptor interactions were evaluated through a molecular docking study. To evaluate their inhibitory activities against EGFR and SRC kinase, in vitro enzyme assays were used. Anticancer potencies were determined using lung, breast, prostate (A549, MCF6, PC3) cancer cell lines. Compounds were also tested against normal (HEK293) cell line to evaluate their cyctotoxic effects. Although, none of compounds showed stronger inhibition compared to osimertinib in the EGFR enzyme inhibition studies, compound 16 showed the highest efficacy with an IC50 of 1.026 μM. It also presented potent activity against SRC kinase with an IC50 of 0.002 μM. Among the tested compounds, the urea containing derivatives 6-11 exhibited a strong inhibition profile (80.12-89.68%) against SRC kinase in comparison to the reference compound dasatinib (93.26%). Most of the compounds caused more than 50% of cell death in breast, lung and prostate cancer cell lines and weak toxicity for normal cells in comparison to reference compounds osimertinib, dasatinib and cisplatin. Compound 16 showed strong cytotoxicity on lung and prostate cancer cells. Treatment of prostate cancer cell lines with the most active compound, 16, significantly increased the caspase-3 (8-fold), caspase-8 (6-fold) and Bax (5.7-fold) levels and decreased the Bcl-2 level (2.3-fold) compared to the control group. These findings revealed that the compound 16 strongly induces apoptosis in the prostate cancer cell lines. Overall kinase inhibition, cytotoxicity and apoptosis assays presented that compound 16 has dual inhibitory activity against SRC and EGFR kinases while maintaining low toxicity against normal cells. Other compounds also showed considerable activity profiles in kinase and cell culture assays.

Design and Synthesis of Gefitinib Derivatives as Potential Drugs fo r Cancer Treatment: Antiproliferative Activity, Molecular Docking, and ADMET Prediction

Background: Non-small cell lung cancer is one of the most common cancers worldwide, and targeted chemotherapy has become a kind of the main treatment. Gefitinib, the most widely studied targeted agent in non-small cell lung cancer, is an orally active tyrosine kinase inhibitor. However, gefitinib inevitably generates acquired drug resistance, leading to treatment failure. Objective: A new class of compounds containing 4-anilinoquinazoline lead structure was designed and synthesized by modifying the structure of gefitinib. These compounds are expected to exert better anticancer activity and better binding to the EGFR-TK domain, enrich the structure of 4-anilinoquinazoline derivatives and inspire further structural modifications. Methods: The antiproliferative activity of nine derivatives was determined in three cancer cell lines (A549, PC9, and HepG2) using the MTT method. The ADMET profile of all compounds was predicted, and the binding affinity of the compounds (5 and 6) to EGFR was predicted by Schrödinger. In addition, the effect of these compounds (3-6) in inducing apoptosis in HepG2 cells was also studied. Results: Four (3, 5, 6 and 9) of the newly synthesized derivatives exhibited superior antiproliferative activity against A549 to gefitinib (IC50 = 12.64 ± 3.59 μM), with compound 5 having the best activity (IC50 = 7.39 ± 1.24 μM). Moreover, the ability of compounds (3-6) to induce HepG2 cell apoptosis was significantly better than that of gefitinib. Conclusion: Nine structures (compounds 2-10) were synthesized and characterized, and compound 5 had the best antiproliferative activity. Compound 3 possessed the best ability to induce HepG2 apoptosis. Also, ADMET calculations were performed in silico, and the results revealed that compound 3 has more suitable characteristics as a potential drug candidate.

Novel Amide Functionalized Trifluoromethyl thieno[2,3-b]pyridine Derivatives: Anti-cancer Activity and Molecular Docking Studies

Abstract: Our primary research objective is to create and formulate small ring heterocycles with enhanced biological efficacy. Amide functionalized trifluoromethyl thieno[2,3-b]pyridine derivatives as a series were prepared starting from reaction between 1,3 di-ketone and thiocyanoacetamide and obtained pyridine 3. Compound 3 reacts with bromoethyl acetate and obtained compound 4, further compound 4 on reaction with diverse substituted aromatic and aliphatic amines to get amide derivatives 5a-d, 6a-d and 7a-h. All the final compounds evaluated for anti cancer activity against four human cancer cell lines such as ‘HeLa - Cervical cancer (CCL-2); COLO 205- Colon cancer (CCL- 222); HepG2 - Liver cancer (HB-8065); MCF7 - Breast cancer (HTB-22)’ and promising compounds 7d, 7e and 7f have been identified. For compounds 7d, 7e and 7f molecular docking interactions have been identified.

The Therapeutic Effects of Bromelain against Colorectal Cancer: A Systematic Review

Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Objective: Considering the side effects of chemotherapy treatments, we reviewed the anti-cancer effects and mechanisms of bromelain on colon cancer cells in this study. Methods: The PRISMA guidelines were followed in the design of this systematic review. Various databases, including PubMed, Web of Science, Cochrane Library, and Scopus, were thoroughly searched. Finally, 14 articles were retrieved after considering the study's inclusion and exclusion criteria. The desired data were extracted, entered into an Excel file, and the study results were reviewed. Results: According to the included studies, bromelain can significantly reduce the survival and death of cloned cancer cells through different mechanisms. These mechanisms include impeding tumor growth and metastasis by reducing mucins production/secretion and increasing/reducing reactive oxygen species (ROS) production. Moreover, bromelain induces apoptosis via reduced expression of Bcl-2, extracellular signal-related kinase (ERK), Akt, activation caspase system (caspase-3, 7, 8, and 9), and extranuclear p53. Ferroptosis was another mechanism of causing cell death. In addition, bromelain activates the autophagy pathway, lysosome formation, and deregulation of other autophagyrelated proteins. Conclusion: Bromelain effectively inhibits colon cancer cells' growth, proliferation, and metastasis and reduces their survival by different mechanisms. Therefore, after examining clinical studies, it can be used as an effective drug for treating CRC.

Mitochondrial Proteins as Metabolic Biomarkers and Sites for Therapeutic Intervention in Primary and Metastatic Cancers

Abstract: Accelerated aerobic glycolysis is one of the main metabolic alterations in cancer, associated with malignancy and tumor growth. Although glycolysis is one of the most studied properties of tumor cells, recent studies demonstrate that oxidative phosphorylation (OxPhos) is the main ATP provider for the growth and development of cancer. In this last regard, the levels of mRNA and protein of OxPhos enzymes and transporters (including glutaminolysis, acetate and ketone bodies catabolism, free fatty acid β-oxidation, Krebs Cycle, respiratory chain, phosphorylating system- ATP synthase, ATP/ADP translocator, Pi carrier) are altered in tumors and cancer cells in comparison to healthy tissues and organs, and non-cancer cells. Both energy metabolism pathways are tightly regulated by transcriptional factors, oncogenes, and tumor-suppressor genes, all of which dictate their protein levels depending on the micro-environmental conditions and the type of cancer cell, favoring cancer cell adaptation and growth. In the present review paper, variation in the mRNA and protein levels as well as in the enzyme/ transporter activities of the OxPhos machinery is analyzed. An integral omics approach to mitochondrial energy metabolism pathways may allow for identifying their use as suitable, reliable biomarkers for early detection of cancer development and metastasis, and for envisioned novel, alternative therapies.

An Insight into Mesoporous Silica Nanoparticles: Ray of Hope for Cancer Management

Abstract: Cancer is one of the fatal diseases leading to a high mortality rate. The conventional formulations available for the treatment of cancer are associated with several drawbacks. The major ones are increased side effects due to improper tumor selectivity, metastasis of cancer cells and development of multi-drug resistance to available chemotherapeutic drugs. The development of nanobased formulations for the treatment of cancer has been found to be beneficial up to a great extent. Mesoporous Silica nanoparticles are one of the nanotechnology-based formulations that could overcome major disadvantages associated with conventional therapy, such as metastasis, multi-drug resistance and side effects to normal cells. MSN-based nanoformulations could provide dual therapeutic effects against cancer cells. Due to their small size and large surface, which could be functionalized by using different targeting and therapeutic moieties, they provide targeted and enhanced drug delivery. This review highlights Mesoporous silica nanoparticles along with their properties, drug encapsulation and various applications in drug delivery, such as multi-targeting strategy, and multimodal combined therapy by using ultrasound, photodynamic etc. In the future, MSN-based nanomedicines could be used to develop other innovative strategies for cancer treatment.

Strategies to enhance the response of liver cancer to pharmacological treatments.

In contrast to other types of cancers, there is no available efficient pharmacological treatment to improve the outcomes of patients suffering from major primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation is partly due to the existence in these tumors of many different and synergistic mechanisms of resistance, accounting for the lack of response of these patients, not only to classical chemotherapy but also to more modern pharmacological agents based on the inhibition of tyrosine kinase receptors (TKIs) and the stimulation of the immune response against the tumor using immune checkpoint inhibitors (ICIs). This review summarizes the efforts to develop strategies to overcome this severe limitation, including searching for novel drugs derived from synthetic, semisynthetic, or natural products with vectorial properties against therapeutic targets to increase drug uptake or reduce drug export from cancer cells. Besides, immunotherapy is a promising line of research that is already starting to be implemented in clinical practice. Although less successful than in other cancers, the foreseen future for this strategy in treating liver cancers is considerable. Similarly, the pharmacological inhibition of epigenetic targets is highly promising. Many novel "epidrugs," able to act on "writer," "reader," and "eraser" epigenetic players, are currently being evaluated in preclinical and clinical studies. Finally, gene therapy is a broad field of research in the fight against liver cancer chemoresistance, based on the impressive advances recently achieved in gene manipulation. In sum, although the present is still dismal, there is reason for hope in the non-too-distant future.

Redistribution of Defective Mitochondria-mediated Dihydroorotate Dehydrogenase Imparts 5-Fluorouracil Resistance in Colorectal Cancer

Although 5-fluorouracil (5-FU) is the primary chemotherapy treatment for colorectal cancer (CRC), its efficacy is limited by drug resistance. Ferroptosis activation is a promising treatment for 5-FU-resistant cancer cells; however, potential therapeutic targets remain elusive. This study investigated ferroptosis vulnerability and dihydroorotate dehydrogenase (DHODH) activity using stable, 5-FU-resistant CRC cell lines and xenograft models. Ferroptosis was characterized by measuring malondialdehyde levels, assessing lipid metabolism and peroxidation, and using mitochondrial imaging and assays. DHODH function is investigated through gene knockdown experiments, tumor behavior assays, mitochondrial import reactions, intramitochondrial localization, enzymatic activity analyses, and metabolomics assessments. Intracellular lipid accumulation and mitochondrial DHODH deficiency led to lipid peroxidation overload, weakening the defense system of 5-FU-resistant CRC cells against ferroptosis. DHODH, primarily located within the inner mitochondrial membrane, played a crucial role in driving intracellular pyrimidine biosynthesis and was redistributed to the cytosol in 5-FU-resistant CRC cells. Cytosolic DHODH, like its mitochondrial counterpart, exhibited dihydroorotate catalytic activity and participated in pyrimidine biosynthesis. This amplified intracellular pyrimidine pools, thereby impeding the efficacy of 5-FU treatment through molecular competition. These findings contribute to the understanding of 5-FU resistance mechanisms and suggest that ferroptosis and DHODH are promising therapeutic targets for patients with CRC exhibiting resistance to 5-FU.

Recent Updates on Oncogenic Signaling of Aurora Kinases in Chemosensitive, Chemoresistant Cancers: Novel Medicinal Chemistry Approaches for Targeting Aurora Kinases

The Aurora Kinase family (AKI) is composed of serine-threonine protein kinases involved in the modulation of the cell cycle and mitosis. These kinases are required for regulating the adherence of hereditary-related data. Members of this family can be categorized into aurora kinase A (Ark-A), aurora kinase B (Ark-B), and aurora kinase C (Ark-C), consisting of highly conserved threonine protein kinases. These kinases can modulate cell processes such as spindle assembly, checkpoint pathway, and cytokinesis during cell division. The main aim of this review is to explore recent updates on the oncogenic signaling of aurora kinases in chemosensitive/chemoresistant cancers and to explore the various medicinal chemistry approaches to target these kinases. We searched Pubmed, Scopus, NLM, Pubchem, and Relemed to obtain information pertinent to the updated signaling role of aurora kinases and medicinal chemistry approaches and discussed the recently updated roles of each aurora kinases and their downstream signaling cascades in the progression of several chemosensitive/chemoresistant cancers; subsequently, we discussed the natural products (scoulerine, Corynoline, Hesperidin Jadomycin-B, fisetin), and synthetic, medicinal chemistry molecules as aurora kinase inhibitors (AKIs). Several natural products' efficacy was explained as AKIs in chemosensitization and chemoresistant cancers. For instance, novel triazole molecules have been used against gastric cancer, whereas cyanopyridines are used against colorectal cancer and trifluoroacetate derivatives could be used for esophageal cancer. Furthermore, quinolone hydrazine derivatives can be used to target breast cancer and cervical cancer. In contrast, the indole derivatives can be preferred to target oral cancer whereas thiosemicarbazone-indole could be used against prostate cancer, as reported in an earlier investigation against cancerous cells. Moreover, these chemical derivatives can be examined as AKIs through preclinical studies. In addition, the synthesis of novel AKIs through these medicinal chemistry substrates in the laboratory using in silico and synthetic routes could be beneficial to develop prospective novel AKIs to target chemoresistant cancers. This study is beneficial to oncologists, chemists, and medicinal chemists to explore novel chemical moiety synthesis to target specifically the peptide sequences of aurora kinases in several chemoresistant cancer cell types.

Therapeutic, chemo-sensitizing, protective effects of natural products against cancerous cells: Preclinical and clinical studies

Therapeutic, chemo-sensitizing, protective effects of natural products against cancerous cells: Preclinical and clinical studies

Oncogenic alterations of metabolism associated with resistance to chemotherapy.

Metabolic reprogramming in cancer cells is a strategy to meet high proliferation rates, invasion, and metastasis. Also, several researchers indicated that the cellular metabolism changed during the resistance to chemotherapy. Since glycolytic enzymes play a prominent role in these alterations, the ability to reduce resistance to chemotherapy drugs is promising for cancer patients. Oscillating gene expression of these enzymes was involved in the proliferation, invasion, and metastasis of cancer cells. This review discussed the roles of some glycolytic enzymes associated with cancer progression and resistance to chemotherapy in the various cancer types.

Nano-drug-based Targeted Therapy Alleviates Ferroptosis-induced Liver Toxicity

Abstract: Iron is an essential inorganic element for an organism, with several metabolic activities. The glycoproteins ferritin and transferrin, which assist in carrying iron to various body parts, are used to store iron. In terms of iron uptake, storage, and excretion, equilibrium should be preserved. Ferroptosis is an iron-dependent form of cell death with traits like lipid peroxidation buildup and ROS generation. It is distinct from other forms of cell death visually and biochemically. Many cancer cells block ferroptosis by controlling different cell survival pathways. Compared to healthy, normal cells, cancer cells are more dependent on iron. A subgroup of tumor cells known as cancer stem cells has stem-like characteristics. These are in charge of metastasis and recurrence. The liver plays a significant part in the body's detoxifying process and is the primary iron storage organ. Numerous liver disorders are frequently accompanied by excessive iron accumulation. Due to excessive iron deposits, the liver is more vulnerable to oxidative damage, which can occasionally result in liver failure. Chemotherapy, which involves administering several medications to treat cancer, may be hazardous to the body's other cells. The ferroptosis condition and high iron accumulation can potentially impair liver function. A tailored drug delivery method may ameliorate the impact of excessive iron accumulation and favorably correlate with liver damage, consequently enhancing liver function.

Ebselen: A Review on its Synthesis, Derivatives, Anticancer Efficacy and Utility in Combating SARS-COV-2.

Ebselen is a selenoorganic chiral compound with antioxidant properties comparable to glutathione peroxidase. It is also known as 2-phenyl-1,2-benzisoselenazol-3(2H)-one. In studies examining its numerous pharmacological activities, including antioxidant, anticancer, antiviral, and anti-Alzheimer's, ebselen has demonstrated promising results. This review's primary objective was to emphasize the numerous synthesis pathways of ebselen and their efficacy in fighting cancer. The data were collected from multiple sources, including Scopus, PubMed, Google Scholar, Web of Science, and Publons. The starting reagents for the synthesis of ebselen are 2-aminobenzoic acid and N-phenyl benzamide. It was discovered that ebselen has the ability to initiate apoptosis in malignant cells and prevent the formation of new cancer cells by scavenging free radicals. In addition, ebselen increases tumor cell susceptibility to apoptosis by inhibiting TNF-α mediated NF-jB activation. Ebselen can inhibit both doxorubicin and daunorubicin-induced cardiotoxicity. Allopurinol and ebselen administered orally can be used to suppress renal ototoxicity and nephrotoxicity. Due to excessive administration, diclofenac can induce malignancy of the gastrointestinal tract, which ebselen can effectively suppress. Recent research has demonstrated ebselen to inhibit viral function by binding to cysteine-containing catalytic domains of various viral proteases. It was discovered that ebselen could inhibit the catalytic dyad function of Mpro by forming an irreversible covalent bond between Se and Cys145, thereby altering protease function and inhibiting SARS-CoV-2. Ebselen may also inhibit the activation of endosomal NADPH oxidase of vascular endothelial cells, which is believed to be required for thrombotic complications in COVID-19. In this review, we have included various studies conducted on the anticancer effect of ebselen as well as its inhibition of SARS-CoV-2.

Anticancer activity of Aucklandia costus Falc. terpenes: Targeting MDM2 protein inhibition for therapeutic advancements

Context: Protein 53 (p53) is a well-known tumor suppressor protein, while murine double minute 2 (MDM2) acts as a negative regulator of p53, leading to p53 inactivation and cancer development. Aucklandia costus Falc. or Saussurea lappa contains bioactive compounds, particularly terpenoids, known for their anticancer activity against various cancer cells. Targeting the p53-MDM2 protein interaction and inhibiting MDM2 are crucial strategies in cancer therapy. Aims: To analyze the anticancer properties of A. costus terpenes against MDM2 protein. Methods: The compounds costunolide, dehydrocostus lactone, lappadilactone, and cynaropicrin were docked with MDM2 (PDB ID: 4HG7) using AutoDockTools 1.5.6. Additionally, the physicochemical, pharmacokinetic, and toxicity properties were predicted using pkCSM. Results: Lappadilactone exhibited the highest binding energy value, surpassing both the control and the native ligand. Following lappadilactone, cynaropicrin, costunolide, and dehydrocostus lactone displayed decreasing binding energies. When assessing ADMET properties with pkCSM, all compounds exhibited good permeability, suggesting their ability to penetrate intestinal cell membranes, and showed no signs of hepatotoxicity. Conclusions: Lappadilactone emerges as a promising candidate with high intestinal absorption, distinctive distribution characteristics, and a lack of mutagenic or hepatotoxic effects.

Combinatorial Inhibition of Complement Factor D and BCL2 for Early-Onset Colorectal Cancer.

The tumor immune microenvironment is distinct between early-onset and late-onset colorectal cancer, which facilitates tumor progression. We previously identified several genes, including complement factor D, as having increased expression in patients with early-onset colorectal cancer. This study aimed to assess and validate the differential expression of immune genes in early-onset and late-onset colorectal cancer. We also aimed to test known drugs targeting genes increased in early-onset colorectal cancer in preclinical mouse models. A retrospective cohort study with analysis was performed using tumor RNA from formalin-fixed paraffin-embedded cell culture and immunohistochemistry to validate gene expression and function and in vivo preclinical tumor study to assess drug efficacy. The Oregon Colorectal Cancer Registry was queried to identify patients with colorectal cancer. The study included 67 patients with early-onset colorectal cancer and 54 patients with late-onset colorectal cancer. Preclinical animal models using the HCT-116 colon cancer cell line were treated with the complement factor D inhibitor danicopan and the BCL2 inhibitor venetoclax, or with vehicle controls. Elevated RNA signatures using NanoString data were evaluated by the retrospective cohort. When inhibiting these markers in the mouse preclinical model, tumor volume and weight were the main outcome measures. After updating our sample size from our previously published data, we found that complement factor D and BCL2, genes with known function and small molecule inhibitors, are elevated in patients with early-onset colorectal cancer. When inhibiting these markers with the drugs danicopan and venetoclax in a mouse model, we found that the combination of these drugs decreased tumor burden but also resulted in toxicity. This study is limited by a small sample size and a subcutaneous tumor model. Combinatorial inhibition of early-onset associated genes complement factor D and BCL2 slows the growth of early-onset colorectal cancer in a mouse preclinical model. See Video Abstract . ANTECEDENTES:El microambiente inmunológico del tumor es distinto entre el cáncer colorrectal de aparición temprana y el de aparición tardía, lo que facilita la progresión de dicho tumor. Anteriormente identificamos varios genes, incluidos el factor D-Complementario, con una mayor expresión en pacientes con cáncer colorrectal de aparición temprana.OBJETIVO:El presente estudio tuvo como objetivo el evaluar y validar la expresión diferenciada de genes inmunes en casos de cáncer colorrectal de aparición temprana y tardía. También nos propusimos evaluar los fármacos conocidos dirigidos sobre los genes aumentados en el cáncer colorrectal de aparición temprana en modelos pre-clínicos en ratones.DISEÑO:Estudio de cohortes con análisis retrospectivo utilizando el ARN tumoral procedente de cultivos celulares fijados con formalina e incluidos en parafina, y el analisis por inmunohistoquímica para validar la expresión y la función genética. Se realizó el estudio pre-clínico de los tumores in vivo para evaluar la eficacia de los fármacos.AJUSTES:Se consultó el Registro de Oregon de casos de Cáncer Colorrectal para encontrar los pacientes afectados.SUJETOS:67 pacientes con cáncer colorrectal de aparición temprana y 54 pacientes con cáncer colorrectal de aparición tardía.INTERVENCIONES (SI LAS HUBIESE):Los modelos animales pre-clínicos que utilizaron la línea celular de cáncer de colon HCT-116 se trataron con el inhibidor del factor D-Complementario o Danicopan y con el inhibidor de BCL-2 o Venetoclax, ambos con control del transportador.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron las firmas de ARN elevadas utilizando los datos del NanoString a partir de la cohorte retrospectiva. Al inhibir estos marcadores del modelo pre-clínico en los ratones, el volumen y el peso del tumor fueron las principales medidas de resultado.RESULTADOS:Después de actualizar el tamaño de nuestra muestra a partir de datos publicados con anterioridad, encontramos que el factor D-Complementario y BCL-2, genes con función conocida e inhibidores de moléculas pequeñas, se encuentran elevados en aquellos pacientes con cáncer colorrectal de aparición temprana. Al inhibir estos marcadores con los medicamentos Danicopan y Venetoclax en el modelo de ratones vivos, encontramos que la combinación de estos dos farmacos disminuyó la carga tumoral pero también produjo toxicidad.LIMITACIONES:Estudio limitado por un tamaño de muestra pequeño y el modelo de tumor subcutáneo.CONCLUSIONES:La inhibición combinada de genes asociados de aparición temprana, el factor D-Complementario y el BCL-2, enlentecen el crecimiento del cáncer colorrectal de aparición temprana del modelo preclínico en ratones. (Traducción-Dr. Xavier Delgadillo ).

Apigenin is an anoikis sensitizer with strong anti-metastatic properties in experimental breast cancer

Loss of susceptibility to anoikis signals is a crucial step in metastasis. Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management. In this study, we have conducted a rationalized screening to search for novel leading anoikis sensitizer from daily foods. Among 19 tested dietary phytochemicals, the best results were obtained with apigenin, a natural component of celery. Phenotypically, apigenin sensitized breast cancer cells to anoikis, lowered the number of circulating tumor cells, and protected against breast cancer metastasis to lung in mice. Mechanistically, we demonstrated that the thromboxane A2 (TXA2)-TXA2 receptor (TP) axis has a critical role in acquired anoikis resistance by activating PI3K-Akt signaling pathway. Blockage of TXA2 signaling up-regulated p53 as well as its target gene p21, caused a G1 phase arrest, and finally led to apoptosis in breast cancer cells. TXA2 level was positively correlated with breast cancer cell anoikis rate, and apigenin significantly inhibited TXA2 biosynthesis in vitro and in vivo. Collectively, we identified apigenin as a potent anoikis sensitizer with anti-metastatic properties in a mouse model of breast cancer, and these findings might provide a rationale for introducing apigenin supplementation to breast cancer patients.