Antineoplastic Activity Research Articles

Temozolomide alleviates breast carcinoma via the inhibition of EGFR/ERK/ MMP-1 pathway with induction of apoptotic events.

To evaluate the chemotherapeutic activity of temozolomide counter to mammary carcinoma. In-vitro anticancer activity has been conducted on MCF7 cells, and mammary carcinoma has been induced in Wistar rats by introduction of 7, 12-Dimethylbenz(a)anthracene (DMBA), which was sustained for 24 weeks. Histopathology, immunohistochemistry, cell proliferation study and apoptosis assay via TUNEL method was conducted to evaluate an antineoplastic activity of temozolomide in rat breast tissue. IC50 value of temozolomide in MCF7 cell has been obtained as 103μM, which demonstrated an initiation of apoptosis. The temozolomide treatment facilitated cell cycle arrest in G2/M and S phase dose dependently. The treatment with temozolomide suggested decrease of the hyperplastic abrasions and renovation of the typical histological features of mammary tissue. Moreover, temozolomide therapy caused the downregulation of epidermal growth factor receptor, extracellular signal-regulated kinase, and metalloproteinase-1 expression and upstream of p53 and caspase-3 proliferation to indicate an initiation of apoptotic events. The occurrence of mammary carcinoma has been significantly decreased by activation of apoptotic pathway and abrogation of cellular propagation that allowable for developing a suitable mechanistic pathway of temozolomide in order to facilitate chemotherapeutic approach.

PH-responsive niosome-based nanocarriers of antineoplastic agents.

Differences in pH between the tumour interstitium and healthy tissues can be used to induce conformational changes in the nanocarrier structure, thereby triggering drug release at the desired site. In the present study, novel pH-responsive nanocarriers were developed by modifying conventional niosomes with hexadecyl-poly(acrylic acid)n copolymers (HD-PAAn). Niosomal vesicles were prepared by the thin film hydration method using Span 60, Span 60/Tween 60 and cholesterol as main constituents, and HD-PAA modifiers of different concentrations (0.5, 1, 2.5, 5 mol%). Next, two model substances, a water-soluble fluorescent dye (calcein) and a hydrophobic agent with pronounced antineoplastic activity (curcumin), were loaded in the aqueous core and hydrophobic membrane of the elaborated niosomes, respectively. Physicochemical properties of blank and loaded nanocarriers such as hydrodynamic diameter (Dh), size distribution, zeta potential, morphology and pH-responsiveness were investigated in detail. The cytotoxicity of niosomal curcumin was evaluated against human malignant cell lines of different origins (MJ, T-24, HUT-78), and the mechanistic aspects of proapoptotic effects were elucidated. The formulation composed of Span 60/Tween 60/cholesterol/2.5% HD-PAA17 exhibited optimal physicochemical characteristics (Dh 302 nm; ζ potential -22.1 mV; high curcumin entrapment 83%), pH-dependent drug release and improved cytotoxic and apoptogenic activity compared to free curcumin.

Directionally non-rotating electric field therapy delivered through implanted electrodes as a glioblastoma treatment platform: A proof-of-principle study.

While directionally rotating tumor-treating fields (TTF) therapy has garnered considerable clinical interest in recent years, there has been comparatively less focus on directionally non-rotating electric field therapy (dnEFT). We explored dnEFT generated through customized electrodes as a glioblastoma therapy in in vitro and in vivo preclinical models. The effects of dnEFT on tumor apoptosis and microglia/macrophages in the tumor microenvironment were tested using flow-cytometric and qPCR assays. In vitro, dnEFT generated using a clinical-grade spinal cord stimulator showed antineoplastic activity against independent glioblastoma cell lines. In support of the results obtained using the clinical-grade electrode, dnEFT delivered through a customized, 2-electrode array induced glioblastoma apoptosis. To characterize this effect in vivo, a custom-designed 4-electrode array was fabricated such that tumor cells can be implanted into murine cerebrum through a center channel equidistant from the electrodes. After implantation with this array and luciferase-expressing murine GL261 glioblastoma cells, mice were randomized to dnEFT or placebo. Relative to placebo-treated mice, dnEFT reduced tumor growth (measured by bioluminescence) and prolonged survival (median survival gain of 6.5 days). Analysis of brain sections following dnEFT showed a notable increase in the accumulation of peritumoral macrophage/microglia with increased expression of M1 genes (IFNγ, TNFα, and IL-6) and decreased expression of M2 genes (CD206, Arg, and IL-10) relative to placebo-treated tumors. Our results suggest therapeutic potential in glioblastoma for dnEFT delivered through implanted electrodes, supporting the development of a proof-of-principle clinical trial using commercially available deep brain stimulator electrodes.

PHARMACOLOGICAL INVESTIGATION IN ANTICANCER AND ANTIOXIDANT PROPERTY OF CHRYSANTHEMUM MORIFOLIUM RAMAT.

Chrysanthemum morifolium Ramat., commonly referred to as the decorative chrysanthemum or simply mum, has served ornamental and therapeutic objectives historically. Traditionally employed to assuage inflammation, fever, and hypertension, modern exploration has paid particular focus to its conceivable function as an antineoplastic and antioxidant ingredient. Its bioactive mixtures, incorporating flavonoids and polyphenols, have proven potential in discouraging malignant cell proliferation, stimulating apoptosis, and bettering antioxidant safeguards.Various tactics were utilized in the research to investigate CM's pharmacological impacts. Plant extracts were ready using methanol, and their cytotoxicity was evaluated using cell viability assays (MTT, Crystal Violet, Trypan Blue). IC50 values were calculated for HeLa and HepG2 cancerous cell lines. Moreover, antioxidant properties were assessed using catalase (CAT), ascorbate peroxidase (APOX), and glutathione reductase (GSH) assays. Enzyme-linked immunosorbent assays (ELISA) measured fluctuations in p53 and VEGF levels. CM revealed dose-dependently cytotoxic impacts against HeLa and HepG2 cells, with notably reductions in cell viability and heightened cell death seen at elevated concentrations. IC50 values indicated powerful antineoplastic action while sparing noncancerous 3T3 cells. Antioxidant assays uncovered enhanced CAT, APOX, and GSH activities in cancerous cells treated with CM, proposing a role in oxidative stress supervision.Chrysanthemum morifolium Ramat. puts forth encouraging anticancer properties through selective cytotoxicity and apoptotic induction in cancerous cells, backed by heightened antioxidant defenses. Its safety profile in normal cells emphasizes its potential as a therapeutic agent with diminished side effects. However, further exploration is necessary to elucidate the underlying molecular mechanisms and validate its efficacy in animal models and clinical trials. These discoveries underscore CM as a candidate for developing targeted cancer therapies and enhancing overall human health.

Development and validation of a liquid chromatography-tandem mass spectrometry method for the quantification of the acetyl-coenzyme A competitive p300/CBP catalytic inhibitor A-485 in biological samples.

The small molecule A-485 competitively inhibits the histone acetyltransferase domain of CBP (cyclic-adenosine monophosphate response element-binding protein)/p300. Apart from its antineoplastic activity, researchers are exploring its potential benefits in treating osteoporosis and its impact on energy metabolism. However, so far, only limited pharmacokinetic data are available, and the crucial determination of A-485 concentration in various biological materials with small sample volumes remains unpublished. A rapid and sensitive LC-tandem mass spectrometry method has been developed and validated to quantify A-485 in mouse serum and tissue. In this method, serum samples underwent precipitation with acetonitrile, while cell lysates were appropriately diluted. The determination of A-485 utilized a reversed-phase column with a mobile phase gradient, and detection was carried out in multiple reaction monitoring mode. The lower standard sample, with a concentration of 7.8 ng/mL, served as the lower limit of quantification, while the upper standard was established at 1000 ng/mL. A-485 concentrations were assessed in both serum samples and the lysate of all examined tissues, revealing swift metabolic clearance. The analytical method outlined here is deemed appropriate for subsequent studies. The ability to measure the active ingredient in various compartments facilitates the determination of accurate pharmacokinetic parameters. In the event of human use of A-485, the analysis method can be seamlessly transferred to human samples.

Natural isothiocyanates of the genus Capparis as potential agonists of apoptosis and antitumor drugs

BACKGROUND Using gas chromatography-mass spectrometry (GC/MS) analysis, we examined the composition of volatile components present in the yellow and green fruits, seeds, and jam of the scrambling shrub Capparis cartilaginea (C. cartilaginea ). These plant samples were collected from Kibbutz Yotvata in Israel. In all the tested samples, isothiocyanates were identified. Utilizing the PASS program, we ascertained the biological activity of these isothiocyanates present in the Capparis genus. The study results highlighted that all isothiocyanates could potentially act as apoptosis agonists, making them strong candidates for antitumor drugs. This information holds significant value for the fields of medicinal chemistry, pharmacology, and practical medicine. AIM To investigate the volatile components present in the yellow and green fruits, seeds, and jam of the C. cartilaginea shrub using GC/MS analysis, to detect isothiocyanates in all the analyzed plant samples, and to assess the biological activity of these isothiocyanates utilizing the PASS program. METHODS We utilized two primary methods to analyze the volatile compounds present in the yellow and green fruits, seeds, and jams of the C. cartilaginea , native to Israel. We identified biologically active isothiocyanates in these samples. Their anticipated biological activities were determined using the PASS program, with the most dominant activities being apoptosis agonist, anticarcinogenic, and antineoplastic specifically for genitourinary cancer. RESULTS Fruits, seeds, and jams containing isothiocyanates, which exhibit antineoplastic and anticarcinogenic activities, could be suggested for cancer prevention and management. Specific isothiocyanates, with therapeutic potential in this realm, could be recommended as potent anticancer agents in practical medicine following clinical trials. CONCLUSION The discovery that isothiocyanates exhibit potent antineoplastic and anticarcinogenic activities was unexpected. Additionally, certain isothiocyanates demonstrated antifungal, antiviral (specifically against arbovirus), and antiparasitic properties.

Parthenolide As a Therapeutic for Disseminated Canine Neoplasms.

This study provides a unique translational research opportunity to help both humans and dogs diagnosed with diseases that carry dismal prognoses in both species: histiocytic sarcoma (HS), hemangiosarcoma (HSA), and disseminated mastocytosis/mast cell tumor (MCT). Although exceedingly rare in humans, these so called "orphan diseases" are relatively more common in dogs. For these and other more commonplace cancers like lymphoma (Lym), dogs are an excellent translational model for human disease due to remarkably similar disease biology. In this study, assays were performed to assess the therapeutic potential of parthenolide (PTL), a known canonical nuclear factor kappa B (NF-κB) signaling inhibitor with additional mechanisms of antineoplastic activity, including alteration of cellular reduction-oxidation balance. Canine cell lines and primary cells are sensitive to PTL and undergo dose-dependent apoptosis after exposure to drug. PTL exposure also leads to glutathione depletion, reactive oxygen species generation, and NF-κB inhibition in canine cells. Standard-of-care therapeutics broadly synergize with PTL. In two canine HS cell lines, expression of NF-κB pathway signaling partners is downregulated with PTL therapy. Preliminary data suggest that PTL inhibits NF-κB activity of cells and extends survival time in a mouse model of disseminated canine HS. These data support further investigation of compounds that can antagonize canonical NF-κB pathway signaling in these cancers and pave the way for clinical trials of PTL in affected dogs. As dogs are an excellent natural disease model for these cancers, these data will ultimately improve our understanding of their human disease counterparts and hopefully improve care for both species. SIGNIFICANCE STATEMENT: Disseminated neoplasms in human and canine cancers are challenging to treat, and novel therapeutic approaches are needed to improve outcomes. Parthenolide is a promising treatment for histiocytic sarcoma, hemangiosarcoma, and mast cell neoplasia.

Enhanced potency of a chloro-substituted polyaromatic platinum(II) complex and its platinum(IV) prodrug against lung cancer

The present study investigates the anti-neoplastic activity of a platinum (II) complex, Pt(II)5ClSS, and its platinum (IV) di-hydroxido analogue, Pt(IV)5ClSS, against mesenchymal cells (MCs), lung (A549), melanoma (A375) and breast (MDA-MB-231) cancer cells. Both complexes exhibited up to 14-fold improved cytotoxicity compared to cisplatin. NMR was used to determine that ∼25 % of Pt(IV)5ClSS was reduced to Pt(II)5ClSS in the presence of GSH (Glutathione) after 72 h. The complex 1H NMR spectra acquired for Pt(II)5ClSS with GSH shows evidence of degradation and environmental effects (∼30 %). The prominence of the 195Pt peak at ∼ -2800 ppm suggests that a significant amount of Pt(II)5ClSS remained in the mixture. Pt(II)5ClSS and Pt(IV)5ClSS have shown exceptional selectivity to cancer cells in comparison to MCs (IC50 > 150 μM). Western blot analysis of Pt(II)5ClSS and Pt(IV)5ClSS on A549 cells revealed significant upregulation of cleaved PARP-1, BAX/Bcl2 ratio, cleaved caspase 3 and cytochrome thus suggesting apoptosis was induced through the intrinsic pathway. Flow cytometry also revealed significant cell death by apoptosis. Treatment with Pt(II)5ClSS and Pt(IV)5ClSS also showed significant amounts of free radical production while the COMET assay showed that both complexes cause minimal DNA damage. Cellular uptake results via ICP-MS suggest a time-dependent active mode of transport for both complexes with Pt(II)5ClSS being transported at a higher rate compared to Pt(IV)5ClSS. A Dose Escalation Study carried out on BALB/c mice showed that Pt(II)5ClSS and Pt(IV)5ClSS were approximately 8- folds and 12.5-folds, respectively, more tolerated than cisplatin. The present study provides evidence that both complexes may have the characteristics of an efficient and potentially safe anti-tumor drug that could support NSCLC treatment.

Iberverin exhibits antineoplastic activities against human hepatocellular carcinoma via DNA damage-mediated cell cycle arrest and mitochondrial-related apoptosis.

Hepatocellular carcinoma (HCC) is one of the malignant tumors with high incidence and mortality rates in the world. Isothiocyanates (ITCs), bioactive substances present primarily in the plant order Brassicales, have been proved to be promising candidates for novel anti-HCC drugs with chemopreventive and anticancer activities. Iberverin, a predominant ITC isolated from the seeds of oxheart cabbage, has been discovered with anticancer property in lung cancer cells. However, the roles of iberverin in HCC remain elusive. In the present study, the effect and potential mechanisms of iberverin against human HCC were dissected. We demonstrated that low concentrations of iberverin inhibited cell proliferation, suppressed migration and induced mitochondrial-related apoptosis in vitro, and hampered tumorigenicity in vivo, with no obvious toxicity. Furthermore, we found that iberverin treatment induced DNA damage and G2/M phase arrest. Iberverin treatment also caused increased intracellular reactive oxygen species formation and glutathione depletion. Taken together, these results suggest that iberverin promotes mitochondrial-mediated apoptosis and induces DNA damage and G2/M cell cycle arrest in HCC by enhancing oxidative stress. Our findings provide better understanding of the anti-HCC mechanisms of ITCs and the potential for the natural product iberverin as a promising new anti-HCC biotherapeutic.

Synthesis and evaluation of the antitumor activity of 2-amino-4-tetrahydroindazole-substituted benzamide derivatives as HSP90 inhibitors

A new series of 2-cycloalkylamino-4–3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl benzamide analogs was synthesized and evaluated for their in vitro antineoplastic activity. These compounds are analogs of 2-(4-hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl) benzamide (AT533), which has been previously identified as a potent inhibitor of heat shock protein 90 (HSP90). These newly synthesized analogs showed moderate-to-excellent anti-cancer activity against Eca109, A549, and MDA-MB-231 human carcinoma cells. In particular, JD-10, JD-13, and JD-14 demonstrated more potent antineoplastic effects than AT533 in tumor cells. Molecular docking studies indicated that these novel derivatives bind to the ATP-binding pocket of HSP90.

New validated liquid chromatography‐tandem mass spectrometry method for the determination of Dacomitinib in human plasma and its application to a pharmacokinetic study

AbstractDacomitinib, a quinazoline compound, exhibits antineoplastic activity against brain metastasis activities in non‐small cell lung cancer and the central nervous system. In this study, the liquid–liquid extraction method with high‐performance liquid chromatography and tandem mass spectrometry detection method was established and validated for the determination of Dacomitinib in human plasma. Plasma samples were prepared and chromatographic separation was achieved on analytical column Discovery C18 (10 cm × 4.6 mm, 5 μm) with gradient elutes at a flow rate of 0.8 mL/min, using a mobile phase consisting of acetonitrile and ammonium formate. Dacomitinib and dacomitinib D10 (internal standard) were detected by multiple reactions. The method was fully validated according to the United States Food and Drug Administration guidelines. The calibration curve was linear with an excellent correlation coefficient (r2 ˂ 0.99). The method validation steps such as carry‐over, matrix effect, extraction recovery, dilution effect, intra‐inter accuracy, and precision were found within acceptable limits. The method was then applied to a pharmacokinetic study in human plasma. After oral administration, the plasma concentration in different volunteers reached 0.5–250.01 ng/mL. The result established can be applied to the estimation of drugs in human plasma.

Unveiling the therapeutic potential: Evaluation of anti-inflammatory and antineoplastic activity of Magnolia champaca Linn’s stem bark isolate through molecular docking insights

Magnolia champaca Linn. has traditionally been used for medicinal activity in Asia for treating various chronic diseases as well as a source of food, medicines, and other commodities. Due to the long-used history of this plant, the present study was designed to explore the in vitro, in vivo and in silico anti-inflammatory and antineoplastic properties of the methanolic extract and fractions and the pure compound isolated from the most active chloroform fraction (CHF) of the stem bark of the plant. The isolated compound from the most active CHF was characterized and identified as a glycoside, trans-syringin, through chromatographic and spectroscopic (1H-NMR and 13C-NMR) analyses. In the in vitro anti-inflammatory assay, CHF was most effective in inhibiting inflammation and hemolysis of RBCs by 73.91 ± 1.70% and 75.92 ± 0.14%, respectively, induced by heat and hypotonicity compared to standard acetylsalicylic acid. In the egg albumin denaturation assay, CME and CHF showed the highest inhibition by 56.25 ± 0.82% and 65.82 ± 3.52%, respectively, contrasted with acetylsalicylic acid by 80.14 ± 2.44%. In an in vivo anti-inflammatory assay, statistically significant (p < 0.05) decreases in the parameters of inflammation, such as paw edema, leukocyte migration and vascular permeability, were recorded in a dose-dependent manner in the treated groups. In the antineoplastic assay, 45.26 ± 2.24% and 68.31 ± 3.26% inhibition of tumor cell growth for pure compound were observed compared to 73.26 ± 3.41% for standard vincristine. Apoptotic morphologic alterations, such as membrane and nuclear condensation and fragmentation, were also found in EAC cells after treatment with the isolated bioactive pure compound. Such treatment also reversed the increased WBC count and decreased RBC count to normal values compared to the untreated EAC cell-bearing mice and the standard vincristine-treated mice. Subsequently, in silico molecular docking studies substantiated the current findings, and the isolated pure compound and standard vincristine exhibited −6.4 kcal/mol and −7.3 kcal/mol binding affinities with topoisomerase-II. Additionally, isolated pure compound and standard diclofenac showed −8.2 kcal/mol and −7.6 kcal/mol binding affinities with the COX-2 enzyme, respectively. The analysis of this research suggests that the isolated bioactive pure compound possesses moderate to potent anti-inflammatory and antineoplastic activity and justifies the traditional uses of the stem bark of M. champaca. However, further investigations are necessary to analyze its bioactivity, proper mechanism of action and clinical trials for the revelation of new drug formulations.

Malignant gastrointestinal neuroectodermal tumor: a case report and literature review

Introduction and importance: A malignant gastrointestinal neuroectodermal tumor (GNET) is an extremely rare primary malignant mesenchymal tumor of the gastrointestinal tract characterized by EWSR1 gene rearrangement. An optimal systemic treatment strategy for advanced/recurrent GNET has not yet been identified. Case presentation: A 24-year-old male patient was hospitalized with abdominal pain and underwent two operations for a tumor in his small intestine. Immunohistochemistry (IHC) showed strong expression of S-100 protein and SOX 10. Fluorescence in situ hybridization analysis and next-generation sequencing analysis indicated that there were EWSR gene rearrangements and the presence of EWSR-ATP1 gene fusions, respectively. The diagnosis of GNET in the small intestine was confirmed by pathology. The young patient received the fifth-line of apatinib mesylate and the sixth-line of apatinib combined with temozolomide. The two apatinib-containing regimens showed stable disease and progression-free survival of 4.7 months and 3.1 months with single-agent apatinib or apatinib combined with temozolomide, respectively. Clinical discussion: To our best knowledge, this is the first report of malignant GNET treated with apatinib and temozolomide. Apatinib-containing regimens might has antineoplastic activity against GNET. The authors reviewed the relevant reports of previous GNET treatment, summarized the clinicopathological characteristics of GNET, and found that there are no reports of apatinib for backline treatment of GNET. Conclusion: Containing apatinib may provide an additional treatment option for patients with chemotherapy-resistant GNET tumors.

An Explicative Review on the Current Advancement in Schiff Base-Metal Complexes as Anticancer Agents Evolved in the Past Decade: Medicinal Chemistry Aspects.

In the recent era, developments in the field of bio-inorganic chemistry have improved interest in Schiff base complexes (imine scaffolds) for their pharmacological excellence in different areas. Schiff bases are a kind of synthetic molecule that is synthesized by the condensation reaction between a 1o amine and a carbonyl compound. Imine derivatives are also acknowledged for their ability to form complexes with several metals. Due to their wide range of biological activities, they have acquired prominence in the therapeutic and pharmaceutical industries. Inorganic chemists have continued to be intrigued by the vast range of uses of these molecules. Many of them are also thermally stable and have structural flexibility. Some of these chemicals have been discovered to be beneficial as clinical diagnostic agents as well as chemotherapeutic agents. Because of the flexibility of the reactions, these complexes have a wide range of characteristics and applications in biological systems. Anti-neoplastic activity is one of them. This review attempts to draw attention to the most notable examples of these novel compounds, which have excellent anticancer activity against different cancers. The synthetic scheme of these scaffolds, their metal complexes, and the explanation of their anticancer mechanism reported in this paper lead the researchers to design and synthesize more target-specific Schiff base congeners with little or no side effects in the future.

КОМПЛЕКС ФЕНОЛЬНЫХ СОЕДИНЕНИЙ ЭКСТРАКЦИОННЫХ ПРЕПАРАТОВ ИЗ ТРАВЫ ТИМЬЯНА МАРШАЛЛА: ПРОГНОЗИРОВАНИЕ БИОЛОГИЧЕСКОЙ АКТИВНОСТИ МЕТОДОМ IN SILICO

Abstract. Introduction. Currently, Marschall thyme herb (Thymus marschallianus) is currently not an officially used medicinal herbal raw material; however, it is widely used in folk medicine as an analgesic, wound healing, expectorant, and antispasmodic remedy. During phytochemical studies, it was found that the herb contains phenolic compounds represented by the aglycones of flavonoids, such as luteolin or apigenin, their 7-O-glycosides, and hydroxycinnamic acids, such as caffeic and rosmarinic acid. Aim. To predict the biological activity profile and related mechanisms of action of the complex of polyphenol compounds of extractive Marschall thyme herb preparations. Materials and Methods. The research focused on the polyphenolic complex compounds of infusion and tincture from Marschall thyme collected in Altai Krai. For computer-aided prediction of the biological activity of phenolic compounds, the PASS (Prediction of Activity Spectra for Substances) method was used, which allows predicting the activity profile of compounds from the structural formula based on the analysis of the structure–activity relationships. Results and Discussion. The study found that for all compounds, it can be assumed with a high probability to be antioxidant and membrane-protective activity, which may be associated with the suppression of oxidation processes by binding free oxygen, free radicals, and inhibition of free radical formation-responsible enzymes. For caffeic acid, apigenin, luteolin and their glycosides, the predicted types of activity and mechanisms of action aimed at suppressing the inflammatory process. For the sum of flavonoids, the manifestation of cytostatic and antineoplastic activities is expected. Conclusions. Polyphenolic complex of the infusion and tincture of Marschall thyme herb can potentially inhibit oxidative processes, stabilize cell cycle and suppress pathological exudative and proliferative processes. To assess the credibility of the prognosis, the results should be tested in real in vitro and in vivo studies.

Abstract C124: Assessment of the anticancer potential of a natural compound euphol in colorectal cancer from in vitro and in vivo mouse models

Abstract Introduction and objectives: Euphol, a tetracyclic triterpene alcohol, is the main component in the sap of the Euphorbiaceae family of plants in subtropical and tropical regions. It has been reported as a modulator of protein kinases C (PKC) activity and to possess several properties, including anti-inflammatory and, more recently, antineoplastic action. These findings further amplified the therapeutic interest in euphol for cancer prevention and treatment. In the present study, we aimed to explore the in vitro and in vivo antitumor effect of synthetic euphol on colorectal cancer (CRC) to provide insight into euphol-based therapies for cancer patients. Methods: Cytotoxicity potential of commercial synthetic euphol on CRC cell lines (HCT15, LOVO – MSI) and (SW620, HT29 – MSS) and mouse organoids derived from ApcLoxP/+-Cdx2 mice was analyzed by MTS-based viability assay using CellTiterGlo kit. The clonogenic potential of CRC cell lines was assessed following a 10-day treatment with different doses of euphol. Quantitative RT-PCR and Western blot analyses were performed to study the effects of euphol on the gene and protein expression of the PKCs isoforms in CRC cell lines and organoids. In addition, a PDX mouse model was established using a surgical sample from a CRC patient. For in vivo studies, the PDX model and ApcLoxP/+-Cdx2 mice were administered euphol or vehicle by mouth for 10 days to assess the therapeutic effect and 8 weeks to assess the preventive effect, respectively. Results: Treatment with euphol resulted in reduced cell viability in both MSS and MSI CRC cell lines, and mouse organoids, following a 72-hour exposure. Euphol also promoted the reduction of the clonogenic potential of CRC cell lines in a dose-dependent manner. Further, the PKCα, PKCβ, PKCδ, and PKCZ gene and protein expression were stimulated in euphol-treated organoids, compared to control. Notably, we observed a significant decrease in tumor volume and suppressed tumor growth after 10 days of treatment with euphol in a PDX mouse model. Euphol-treated ApcLoxP/+-Cdx2 mice for 8 weeks also showed reduced colonic polyposis compared to untreated mice. Conclusions: These results indicate that synthetic euphol has a cytotoxic potential in inhibiting cell proliferation of CRC cells in both 2D and 3D models, and in vivo models through modulation of the expression of genes involved PKC pathway, thus highlighting the therapeutic potential of euphol for CRC. Citation Format: Ana Laura Vieira Alves, Ana Carolina Martin, Krishna M Sinha, Viviane Aline Oliveira Silva, Renato José da Silva-Oliveira, Silvia A Teixeira, Denise P Guimaraes, Luis Gustavo Romagnolo, Monise Tadin Reis, Fahriye Duzagac, Eduardo Vilar, Rui Manuel Reis. Assessment of the anticancer potential of a natural compound euphol in colorectal cancer from in vitro and in vivo mouse models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C124.

Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity

&lt;p class="MsoNormal" style="margin-top: 6pt; line-height: 13pt; text-align: justify;"&gt;&lt;span lang="EN-US" style="font-size: 10pt; font-family: arial, helvetica, sans-serif;"&gt;Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/&amp;beta;-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future.&lt;/span&gt;&lt;/p&gt;

Novel sulindac derivatives for colorectal cancer chemoprevention that target cGMP phosphodiesterases to suppress Wnt/β-catenin transcriptional activity

&lt;p class="MsoNormal" style="margin-top: 6pt; line-height: 13pt; text-align: justify;"&gt;&lt;span lang="EN-US" style="font-size: 10pt; font-family: arial, helvetica, sans-serif;"&gt;Approximately 28 million individuals in the United States face the risk of developing precancerous colonic adenomas (polyps) and potentially progressing to colorectal cancer (CRC). While a promising strategy for CRC prevention involves pharmacological intervention, such as cancer chemoprevention or interception, currently, there are no FDA-approved drugs capable of preventing the formation or progression of adenomas to adenocarcinoma. Numerous clinical, epidemiological, and preclinical studies have offered compelling evidence supporting the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in CRC chemoprevention. However, the prolonged use of NSAIDs is not FDA-approved due to potential life-threatening toxicities resulting from cyclooxygenase (COX) inhibition and the depletion of physiological prostaglandins. Despite indications that the COX inhibitory activity of NSAIDs may not be essential for their antineoplastic effects, the absence of a well-defined target impeded the development of derivatives that do not inhibit COX. Earlier research suggests that the inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) may be responsible, at least in part, for the antineoplastic activity of the NSAID sulindac. This could potentially offer a novel target for CRC chemoprevention. To identify the cGMP PDE isozyme(s) contributing to the antineoplastic activity of sulindac, we synthesized a chemically diverse library of over 1500 compounds, all sharing the indene scaffold of sulindac. Subsequently, we screened these compounds for their impact on cancer cell growth and PDE inhibitory activity. From this screening, a series of lead compounds emerged. These compounds lacked COX-1 and COX-2 inhibitory activity, surpassing sulindac in potency to inhibit CRC cell growth. Importantly, they demonstrated greater selectivity by not affecting normal cell growth. Through chemical optimization, we identified several development candidates that selectively inhibit PDE5 and/or PDE10. These compounds activate cGMP/PKG signaling, suppressing Wnt/&amp;beta;-catenin transcription. This action counters the growth advantages resulting from APC or CTNNB1 mutations, which are responsible for most human CRCs. This review delves into the scientific literature supporting PDE5 and/or PDE10 as potential targets for CRC chemoprevention or interception. Our findings suggest a promising avenue for developing drugs that may effectively intervene in the progression of colorectal cancer, offering hope for improved preventive strategies in the future.&lt;/span&gt;&lt;/p&gt;

Phenylthiazolidin-4-one piperazine Conjugates: Design, Synthesis, anticancer and antimicrobial studies

In current research study, a series of ten novel phenylthiazolidin-4-one glycinamide conjugates with piperazines compounds (7a-j) were designed by combining the crucial pharmacophoric features from the reported potential anticancer hit molecules, subsequently evaluated for the drug-likeness behaviour. Designed candidates were synthesized, purified, and characterized by non-spectral and spectral methods. Further, compounds were evaluated for anticancer activity against three cells line; as HEP-G2 cells (liver cancer cells line), MDA-MB-231 (breast cancer cells line) and U87MG cells (brain cancer cells line). Compound 7j exhibited encouraging antineoplastic activity against MDA-MB-231 and HEP-G2 cell line with IC50 of 4.02 and 15.04 µM, comparable to positive control, gemcitabine (IC50: 2.81 and 15.94 µM, respectively). The compound 7j displayed better anticancer activity against U87M with IC50 value of 13.96 µM in comparison to gemcitabine (IC50: 34.26 µM). SAR studies of the series illustrating the effect of different substitutions on the anticancer activity is discussed. Further, cytotoxicity of compound 7j was tested against the brain tumour spheroids (MTS), in which it showed significant apoptosis of MTS cells as compared to gemcitabine. To find the mechanistic basis of cytotoxicity, computational studies were performed against the six probable targets, in which compound 7j showed excellent binding affinity towards DHFR and hDHODH targets, illustrating both as probable targets of the compounds. Additionally, the synthesized compounds were tested for antimicrobial activity against bacterial (E. coli and P. aeruginosa) and fungal strains (C. albicans), in which majority of compounds showed moderate to weak activity.

Overall Survival of Warfarin Compared to LMWH/Doacs in Cancer-Associated Venous Thromboembolism: VA Cohort Study

Background: Warfarin has been shown in pre-clinical models to have anti-neoplastic activity. In a population-based study using the SEER-Medicare Linked Database warfarin was associated with improved survival compared to low molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs) in the treatment of cancer-associated thrombosis (CAT). To assess whether the observed survival advantage is consistent in other large cohorts, we performed a matched cohort study utilizing the Veterans Affairs (VA) database. The VA is a large, integrated health care system with comprehensive data for their patients at the individual level, which provides the optimal observational cohort to confirm the novel hypothesis warfarin confers a mortality benefit over LMWH. Method: Using the retrospective data from the VA health care system from 2000-2021, we identified patients with CAT who were &amp;gt; 18 years, had available prescription data for anticoagulation within 30 days of venous thromboembolism (VTE), and survived &amp;gt; 14 days after the index VTE event. Patients were excluded if they had prior diagnosis of VTE or had any anticoagulation prescription prior to the first coded VTE event. The primary outcome was overall survival (OS). Patients were matched 1:1 using nearest neighbor matching on the propensity score. The matching variables included cancer site, cancer stage, date of cancer diagnosis, date of VTE diagnosis, age at VTE diagnosis, gender, race, BMI, Elixhauser-based weighted comorbidity score, and rurality of residential status. Cox proportional-hazards regression was performed to estimate hazard ratios (HR) and 95% confidence intervals. Log-rank test was utilized to estimate the p-value. Subgroup analyses were performed in the largest groups of cancer available in the data set including prostate cancer, lung cancer, gastrointestinal cancer (excluding hepatobiliary cancer), and malignant hematologic neoplasms (including myeloid malignancy, lymphoid malignancy, and multiple myeloma). Finally subgroup analysis was also performed on localized cancer and metastatic disease based on AJCC stage grouping. Result: There were a total of 20,078 patients that met the inclusion and exclusion criteria without missing data. The warfarin cohort consistent of 8383 patients while non-warfarin cohort comprised 11696 patients. Among the non-warfarin cohort, 54% of the patients were prescribed LMWH exclusively and 38% of the patients were prescribed DOAC exclusively within 30days of the VTE diagnosis. The most common malignancies in the cohort included prostate (29.4%), lung (20.9%), gastrointestinal (15.7%) and hematologic malignancies (10.3%). Of patients with solid tumors, 22% had metastatic cancer. Among the VTE events, 33.3% were acute lower extremity deep vein thrombosis, 48.4% were acute pulmonary embolism, and 18.3% were acute upper extremity deep vein thrombosis. After propensity score matching, 8,383 patients were included in the warfarin arm and 8,383 patients in the non-warfarin arm. The median age at VTE diagnosis of the matched cohort was 69 [IQR 63 - 75] and the majority of the patients (96.7%) were male. Warfarin was associated with a significant improvement in OS compared to non-vitamin K antagonists (median OS, 1204 days [95% CI, 1137-1276 days] vs 703 days [95% CI, 665-747 days]; HR 0.79 [95% CI 0.76 - 0.82]; p-value &amp;lt;2x10 -16) (Figure1). The difference was also preserved in gastrointestinal malignancy (HR 0.8 v95% CI 0.73-0.87), lung cancer (HR 0.8, 95% CI 0.79-0.92) and prostate cancer (HR 0.71, 95% CI 0.65-0.77). The survival advantage was preserved in patients with metastatic (HR 0.86, 95% CI 0.78-0.83) and localized cancer (HR 0.80, 95% CI 0.76-0.84) (Figure 2). Conclusion and Relevance: In a population level propensity matched study, warfarin for the treatment of CAT was associated with significantly improved survival over non-vitamin K antagonist anticoagulation in CAT. These provocative finding confirm the previous observation in SEER-Medicare database and have important implications on patient care and health care costs. Further investigation into the biological basis of these findings could potentially lead to biomarker and drug discovery for cancer therapies and prognostication.