Antiproliferative Effects Research Articles

Gastroenteropancreatic Neuroendocrine Tumor with Peritoneal Metastasis: A Review of Current Management.

Peritoneal metastasis in gastroenteropancreatic neuroendocrine tumors poses a significant clinical challenge, with limited data guiding management strategies. We review the existing literature on surgical and systemic treatment modalities for peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors. Surgical interventions, including cytoreductive surgery, have shown promise in improving symptom control and overall survival-particularly in cases in which 70% cytoreduction can be achieved. Hyperthermic intraperitoneal chemotherapy remains controversial due to a paucity of high-level evidence and a lack of consensus for routine use. The use of systemic therapy in the setting of peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors is extrapolated from high-quality evidence for its use in the setting of the solid organ metastasis of this disease. The use of somatostatin analogs for symptom control and some antiproliferative effects is supported by large clinical trials. Additional strong evidence exists for the use of interferon-alpha, everolimus, and sunitinib, particularly in pancreatic neuroendocrine tumors. Cytotoxic chemotherapy and peptide receptor radionuclide therapy may be used in select cases, though as an emerging treatment modality, the optimal sequence of peptide receptor radionuclide therapy within the existing algorithms is unknown. Significant gaps in understanding and standardized management exist, particularly for those patients presenting with peritoneal metastasis, and targeted research to optimize outcomes in this population is needed.

Phytochemical composition and anticancer effect of Akebia trifoliata seed in non-small cell lung cancer A549 cells

BackgroundAkebia trifoliata is a widely distributed medicine and food homology plant. Its fruit is used to treat tumors and the seed’s weight proportion exceeds 50%. However, the anti-tumor effect of A. trifoliata seed remains poorly studied. MethodsUHPLC-Q-Orbitrap-MS was used to identify the chemical components of A. trifoliata seed water extract (WE) and ethanolic extract (EE), and their cytotoxicity was evaluated using MTT assay. Further, colony formation and cell cycle assays examined the anti-proliferative effect of A. trifoliata seed EE. Next, morphology observation, AO/EB staining, Hoechst 33,258 staining, Annexin V-PE/7-AAD staining, and JC-1 assays were employed to detect apoptosis. The influence of A. trifoliata seed EE on A549 cell metastasis was assessed by wound healing and transwell invasion tests. In addition, western blotting and network pharmacology were applied to further analyze its anticancer mechanism. ResultsEighty-two components were characterized from the A. trifoliata seed WE and EE. For anticancer activity, A. trifoliata seed EE exhibited high cytotoxicity against cancer cells A549 (IC50: 52.38 ± 1.04 μg/mL) and NCI-H1299 (IC50: 70.29 ± 0.58 μg/mL) and revealed low cytotoxicity against non-cancer cells MRC-5 (IC50: 101.28 ± 2.84 μg/mL) and L929 (IC50: 113.44 ± 0.55 μg/mL). A. trifoliata seed EE suppressed A549 cell proliferation by inducing S-phase arrest via down-regulation of CDK2 and p21 as well as up-regulation of cyclin E1 and E2. It increased the Bax/Bcl-2 ratio, reduced mitochondrial membrane potential (ΔΨm), activated caspase-9 and caspase-3, cleaved PARP, and triggered apoptosis through the mitochondrial pathway. Besides, it repressed migratory and invasive ability by reducing MMP-2, MMP-9, and N-cadherin levels. ConclusionA. trifoliata seed EE exhibits outstanding anticancer properties and has the exploitation potential as an anticancer drug in the pharmaceutical industry.

Synthesis of Alkyl/Aryloxymethyl Derivatives of 1,2,4-Triazole-3-Carboxamides and Their Biological Activities.

Ribavirin and its analogues exhibit an in vitro antiproliferative effect in cancer cells. In this work, we studied the biological activities of a number of alkyl/aryloxymethyl derivatives of ribavirin's aglycon-1,2,4-triazole-3-carboxamide. Alkyl/arylxymethyl derivatives of 1,2,4-triazole-3-carboxamide with substitutions at the fifth or first position of the triazole ring, were synthesized and their antiproliferative and antimicrobial effects were assessed. For both series, the presence of an antiproliferative effect was investigated, and 1-alkyl/aryloxymethyl derivatives were shown an antimicrobial potential against a Gram-positive bacteria Micrococcus luteus and Gram-negative bacterium Pseudomonas aeruginosa. The obtained results showed that the n-decyloxymethyl derivatives induced leukemia cell death at low micromolar concentrations. We confirmed that n-decyloxymethyl derivatives of ribavirin inhibited the cell cycle progression and induced an accumulation of leukemia cells in the subG1-phase. The molecular docking results suggest that alkyl/aryloxymethyl derivatives may act by inhibiting translation initiation, due to interference with eIF4E assembly. The outcome results revealed that active derivatives (1- or 5-n-decyloxymethyl-1,2,4-triazole-3-carboxamides) can be considered as a lead compound for anticancer treatments.

Enhancing Intrapleural Hyperthermic Chemotherapy for Lung Cancer: Insights from 3D and PDX Models

Background/Objectives: Malignant pleural effusion (MPE) in lung cancer indicates systemically disseminated advanced lung cancer and is associated with poor survival. Intrapleural hyperthermic chemotherapy (IPHC) is a promising treatment for MPE; however, its biological basis is not fully understood. IPHC can enhance anticancer drug efficacy, particularly in drug-resistant cancers. This study investigated the effects of hyperthermia on cisplatin cytotoxicity in lung cancer cell lines, patient-derived tumor cells, and a patient-derived xenograft (PDX) model. Methods: Lung cancer cell lines (A549 and H2170) and patient-derived tumor cells were cultured in 2D/3D systems and treated with cisplatin under varying temperatures (37 °C, 43 °C, and 45 °C) and exposure times (5, 15, and 30 min). Antiproliferative effects were evaluated using LDH and CCK-8 assays. Optimal conditions identified in cell culture experiments were validated using a PDX model; tumor growth inhibition, delay, and protein expression were analyzed post-treatment. Results: Hyperthermia significantly enhanced the antitumor efficacy of cisplatin at 43 °C and 45 °C, with comparable effects under 15 and 30 min exposure. In the PDX model, IPHC showed increased tumor inhibition and necrosis and delayed tumor regrowth, particularly at higher cisplatin doses. Protein expression analysis revealed that hyperthermia decreased EGFR expression and increased levels of apoptosis-related proteins, including cleaved PARP and caspase-3. Conclusions: IPHC with cisplatin demonstrated enhanced antitumor efficacy in vitro models, particularly in drug-resistant lung cancer, indicating its potential as a valuable adjunct to existing treatment regimens for lung cancer and for improving patient outcomes in advanced lung cancer with MPE or pleural metastasis.

Evaluation of Anti-Proliferative and Apoptosis-Inducing Activities of the New Ciprofloxacin Derivative on Human Leukemia NB4 Cells

Backgrounds:: Leukemic stem cells are considered to be the main cause of treatment failure and disease recurrence due to their resistance to most common therapies. Apoptosis induction is one of the highly effective methods for treating cancer. Ciprofloxacin is among the compounds whose antitumor effects have been confirmed. Objectives: In this study, we investigated the anti-proliferative effect and induction of apoptosis by one of the derivatives of this family called 1-Cyclopropyl-6-fluoro-7-[4-(2-{[(1R,2S,5R)- 2- isopropyl-5-methylcyclohexyl]oxy}-2-oxoethyl)-piperazin-1-yl]-4-oxo-1,4-dihydroquinoline-3- carboxylic acid (ICH-CP) on NB4 cell line as an in vitro model of Acute promyelocytic leukemia (APL). NB4 cells were treated using the ICH-CP combination in various concentrations. Methods: The viability of NB4 cells was evaluated by MTT assay, and their morphology of apoptosis was examined by fluorescence microscopy. Flow cytometry and Annexin V/PI staining were used to quantify apoptosis. Finally, the expression of three genes, Bax, Bcl-2, and Survivin was inquired by real-time PCR. Results: According to the results, ICH-CP was able to destroy about 60% of NB4 cells in a dose and time-dependent manner. Light microscopy and fluorescence microscopy studies on treated cells confirmed the induction of apoptosis. Also, the real-time PCR analysis showed that ICH-CP induces apoptosis in the NB4 cell line via the down-regulation of Survivin and Bcl-2, in contrast to the up-regulation of the Bax gene. Conclusion: Based on the present data, it seems that the novel compound can be a good candidate for the treatment of acute myeloid leukemia. Furthermore, it is recommended to evaluate the qualification of ICH-CP as an adjunctive agent for other cancer cell lines.

Antiproliferative effect of wild berries and North-Eastern Siberian bulbous spleen carp on breast cancer cells MCF-7

Introduction. Studies have shown that natural compounds from various plants including berries can have antitumor activity. We examined Phlojodicarpus sibiricus extract as well as homogenates of wild berries such as hawthorn, cranberry, brier; all these plants contain a variety of biologically active compounds: flavonoids, carotenoids, anthocyanins and other polyphenols.Aim. To evaluate cytotoxicity of wild berries and Phlojodicarpus sibiricus growing in Northwestern Siberia in Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line using the МТТ assay.Materials and methods. We examined homogenates of wild berries including Dahurian hawthorn (Crataegus dahurica Koehne), bog cranberry (Oxycoccus microcarpus Turcz.), Yakut brier (Rosa jacutica Juz.) and extract of the above-ground part (leaves, stems) of Phlojodicarpus sibiricus. Cytotoxicity of the prepared homogenates was evaluated on the MCF-7 cell line. For homogenate screening, colorimetric assay for assessing cell metabolic activity МТТ was used.Results. Dahurian hawthorn, bog cranberry and Yakut brier have statistically significant cytotoxic effect on tumor cells at concentration of 100 mg/mL in incubation medium. Among the evaluated berries, Yakut brier demonstrated the highest suppression of MCF-7 cell line growth: at dose 100 mg/mL it decreased it by 80.19 % compared to control. Extract of Phlojodicarpus sibiricus at concentration 10 mg/mL left only 4.95 % of the MCF-7 cells alive.Conclusion. Therefore, wild berries have antiproliferative potential. Being edible, they can be helpful in prevention of oncological diseases. High antiproliferative activity of Phlojodicarpus sibiricus demonstrated by us in this and previous studies indicate that it can be considered a source of effective antitumor compounds.

Molecular mechanisms of novel selective glucocorticoid receptor agonist action in breast cancer cells

Introduction. Glucocorticoids (GC) are widely used in breast cancer (BC) therapy to reduce the side effects of cytostatic drugs and may exhibit antiproliferative effects on luminal BC cells. The biological action of GC is mediated by glucocorticoid receptor (GR) by two mechanisms: transrepression, which determines the therapeutic effect of GC, and transactivation (associated with the development of side effects, resistance to cytotoxic drugs, cancer progression and metastasis). Selective GR agonists (SEGRA) which may selective activate transrepression are a promising alternative to GC to use in combination cancer therapy. One of the most studied SEGRA is Compound A (CpdA). The instability of CpdA limits its use in clinical practice. So recently we performed synthesis and evaluation of biological activities of the CpdA analogue, CpdA-03.Aim. To compare the effects of SEGRA CpdA-03 and CpdA and dexamethasone on proliferative activity of breast cancer cells, as well as receptor nuclear translocation and activation of GR-dependent genes in breast cancer cells.Materials and methods. Luminal (MCF-7) and triple negative (MDA-MB-231) BC cell lines were used. The effect of CpdA-03 on proliferation was evaluated by direct counting of viable cells with trypan blue staining. The effect of the compound on cell distribution by cell cycle phases was assessed by flow cytofluorimetry with propidium iodide staining. Changes in the expression of GR-dependent genes after incubation with CpdA-03 were evaluated by quantitative polymerase chain reaction. Additionally, the ability of the new SEGRA to induce transactivation-associated translocation of the receptor to the nucleus was evaluated by Western blotting.Results. CpdA-03 was shown to suppress proliferation of luminal and triple negative BC cells. This compound causes changes in the expression of a number of GC-inducible genes, but does not stimulate GR phosphorylation and translocation to the nucleus in BC cells.Conclusion. The observed suppression of cell proliferation, as well as the ability of CpdA-03 to reduce gene expression of proteins regulating intercellular adhesion and cell migration, intracellular signaling, stress response, and transcription in BC cells makes it relevant for further development of the drug for use in the combination therapy of cancers including breast cancer.

Structure-Activity Relationship of Potent, Selective, and Orally Bioavailable Molecular Glue Degraders of CK1α.

The original molecular glue degraders (thalidomide, lenalidomide, and pomalidomide) are known to bind to cereblon (CRBN) and alter its surface to induce recruitment, ubiquitination, and degradation of therapeutically valuable neosubstrates (IKZF1, IKZF3, and CK1α). With the aim of understanding and modulating neosubstrate specificity, we recently reported the discovery of SJ3149 (4), a selective and potent molecular glue degrader of CK1α, that is active in multiple cancer cell lines. Herein, we describe the medicinal chemistry efforts that resulted in the discovery of SJ3149 as well as other potent and selective CK1α degraders. We report kinetic profiling and parameters of CK1α degradation, ternary complex, antiproliferative effects, in vitro ADME data, and in vivo pharmacokinetic studies with demonstrated oral bioavailability.

Anticancer Activity of Vitamin D, Lumisterol and Selected Derivatives against Human Malignant Melanoma Cell Lines.

Despite the recent development of improved methods of treating melanoma such as targeted therapy, immunotherapy or combined treatment, the number of new cases worldwide is increasing. It is well known that active metabolites of vitamin D3 and lumisterol (L3) exert photoprotective and antiproliferative effects on the skin, while UV radiation is a major environmental risk factor for melanoma. Thus, many natural metabolites and synthetic analogs of steroidal and secosteroidal molecules have been tested on various cancer cells and in animal models. In this study, we tested the anti-melanoma properties of several natural derivatives of vitamin D3 and L3 in comparison to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). A significant decrease in melanoma cell proliferation and cell mobility was observed for selected derivatives, with (25R)-27-hydroxyL3 showing the highest potency (lowest IC50) in A375 cells but lower potency in SK-MEL-28 cells, whereas the parent L3 failed to inhibit proliferation. The efficacy (% inhibition) by 1,24,25(OH)3D3 and 1,25(OH)2D3 were similar in both cell types. 1,25(OH)2D3 showed higher potency than 1,24,25(OH)3D3 in SK-MEL-28 cells, but lower potency in A375 cells for the inhibition of proliferation. As for 1,25(OH)2D3, but not the other derivatives tested, treatment of melanoma cells with 1,24,25(OH)3D3 markedly increased the expression of CYP24A1, enhanced translocation of the vitamin D receptor (VDR) from the cytoplasm to the nucleus and also decreased the expression of the proliferation marker Ki67. The effects of the other compounds tested were weaker and occurred only under certain conditions. Our data indicate that 1,24,25(OH)3D3, which has undergone the first step in 1,25(OH)2D3 inactivation by being hydroxylated at C24, still shows anti-melanoma properties, displaying higher potency than 1,25(OH)2D3 in SK-MEL-28 cells. Furthermore, hydroxylation increases the potency of some of the lumisterol hydroxy-derivatives, as in contrast to L3, (25R)-27(OH)L3 effectively inhibits proliferation and migration of the human malignant melanoma cell line A375.

α-Mangostin-phytosomes as a plausible nano-vesicular approach for enhancing cytotoxic activity on SKOV-3 ovarian cancer cells

Backgroundα-Mangostin is a major xanthone in Garcinia mangostana L. (Clusiaceae) pericarps. It has promising anti-proliferative potential in different cancer cells; however, it has poor oral bioavailability. Phytosomes are used as a novel nano-based drug delivery system. The aim of this research was to enhance the anti-proliferative potency of α-mangostin by formulating it as α-mangostin-phytosome (α-M-PTMs) and assessing its impact on SKOV-3 ovarian cancer cells in comparison to pure α-mangostin.ResultsThe size and entrapment efficiency of the proposed formulation were optimized using Box–Behnken statistics. The optimized formula was characterized using transmission electron microscope. The binding of α-mangostin to phospholipids was confirmed using Fourier-transform infrared (FTIR) spectroscopy. The optimized α-mangostin-phytosomes formula exhibited enhanced anti-proliferative activity with reference to raw α-mangostin. This was further substantiated by assessing the cell cycle phases that indicated an accumulation of SKOV-3 cells in the sub-G1 phase. Annexin-V staining revealed enhanced apoptotic activity in α-mangostin-phytosome-treated cells. This was associated with upregulation of CASP3 (Caspase-3), BAX (BCL2 Associated X, Apoptosis Regulator) and TP53 as well as down-regulation of BCL2 mRNA (B-Cell Leukemia/Lymphoma 2). Moreover, our data indicated enhanced ROS (Reactive oxygen species) production, cytochrome-C release, and disturbed MMP (mitochondrial membrane potential).ConclusionEncapsulation of α-mangostin in a phytosome nano-formula enhances its anti-proliferative effects in SKOV-3 cells via, at least in part, inducing mitochondrial apoptotic cell death.

IN VITRO ANTICANCER ACTIVITY OF HISTATIN-1 COMBINATION WITH CISPLATIN IN HEAD AND NECK CANCER CELL LINES.

Chemotherapy of head and neck squamous cell carcinoma (HNSCC) is associated with significant side effects. Antimicrobial peptides (AMPs), which are naturally occurring defense molecules like defensin-1 and LL-37 found in human secretions, have demonstrated potential in prompting tumor cell apoptosis and enhancing the effect of chemotherapeutic agents. However, the anticancer potential of histatin has not yet been thoroughly examined. The aim of the study was to explore the anticancer activity of histatin, an AMP present in human saliva and used alone or in combination with cisplatin in HNSCC cell lines. The gene expression of histatin was evaluated in the HSC4 and SCC25 cell lines by qRT-PCR. Cell proliferation was investigated at different concentrations of histatin peptide (His-1), cisplatin, and their combination using an MTT assay. SCC25 cells expressed both HTN1 (histatin-1) and HTN3 (histatin-3), whereas the HSC4 cell line expressed only HTN1. The combination of exogenous His-1 and cisplatin demonstrated a synergistic anti-proliferative effect against the HNSCC cell lines in a dosedependent manner. The combination of low-dose cisplatin and histatin inhibits HNSCC cell proliferation. His-1 sensitizes tumor cells to the cytotoxic effects of cisplatin potentially allowing for a reduction in its effective concentration.

Combination of heme oxygenase-1 inhibitors and temozolomide to improve the anticancer effect in glioblastoma

Heme oxygenase-1 (HO-1) is involved in the oncogenesis of glioblastoma (GBM). In this work, we investigated for the first time how the co-administration (combo) of the HO-1 inhibitors SI1/09 or LS6/42 with temozolomide (TMZ) or temozolomide acid (TMZ Ac) may influence the proliferation of U87MG GBM cell lines. Moreover, two novel TMZ/HO-1 inhibitors codrugs LS8/21 and LS8/24 were synthesised, characterised and tested. Results indicate that the combos TMZ or TMZ Ac with LS6/42, as well as the corresponding LS8/24, are more efficacious in reducing U87MG cell proliferation with respect to reference drugs, allowing a possible reduction of the TMZ dosage and related side effects in clinical practice. The chemical and enzymatic stability of the most potent codrug LS8/24 was evaluated. The observed high potency performed by both combos and LS8/24 in cells suggests that HO-1 inhibition may give additional contribution to the antiproliferative effect of TMZ.

Establishing capsaicin's anti-cancer intricacies in chronic myelogenous leukemia care: insights from human K562 cells

Objective: We aimed to establish capsaicin as a potent natural chemotherapeutic agent in chronic myeloid leukemia by unveiling anti-cancer mechanisms, concentrating at pro-apoptotic and anti-proliferative effects on K562 cells. Methodology: After REC approval, this research proceeded with culturing K562 cells and treatment with serial concentrations of capsaicin for calculation of subsequent 50% Inhibitory Concentration (IC50) values via MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay, expression analysis of gene, comparative analysis of relative gene fold (intrinsic biomarkers caspase-3, caspase-9) as apoptosis mediator biomarkers followed by Quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). Anti-proliferative activity was confirmed via Nitric Oxide (NO) releasing Assay. Results: For K562 cells, the IC50 of capsaicin (12.1 µM) showed high gene expression of intrinsic pro-apoptotic biomarkers caspase-3 and caspase-9 with the relative gene fold of 12.1 and 13.9 respectively. Persistent peaks of NO levels confirmed the anti-proliferative potential of the compounds. Strongest growth inhibitory activity was seen at the peak time of 100-120 min. Conclusion: Capsaicin proved to be a strong pro-apoptotic and anti-proliferative phytochemical agent leading to therapeutic effects against K562 cells. Further studies would help in identifying key molecular intricacies by which capsaicin exhibits diversified anti-cancer potential. Abbreviations: CML - chronic myelogenous leukemia; NO - Nitric oxide; ROS - Reactive Oxygen Species; ROS - Reactive Oxygen Species Keywords: Capsaicin, Pro-apoptotic Effects, Anti-Cancer Mechanisms, K562 cells, Natural Chemotherapeutics Citation: Devi D, Nangdev P, Khaliq HMH, Anique M, Moqaddas A, Aziz O, Javed W. Establishing capsaicin's anti-cancer intricacies in chronic myelogenous leukemia care: insights from human K562 cells. Anaesth. pain intensive care 2024;28(5):830−835; DOI: 10.35975/apic.v28i5.2494 Received: June 26, 2024; Reviewed: August 10, 2024; Accepted: August 16, 2024

Silmitasertib in Combination With Cabozantinib Impairs Liver Cancer Cell Cycle Progression, Induces Apoptosis, and Delays Tumor Growth in a Preclinical Model.

The rising incidence of hepatocellular carcinoma (HCC) is a global problem. Several approved treatments, including immune therapy and multi-tyrosine kinase inhibitors, are used for treatment, although the results are not optimum. There is an unmet need to develop highly effective chemotherapies for HCC. Targeting multiple pathways to attack cancer cells is beneficial. Cabozantinib is an orally available bioactive multikinase inhibitor and has a modest effect on HCC treatment. Silmitasertib is an orally bioavailable, potent CK2 inhibitor with a direct role in DNA damage repair and is in clinical trials for other cancers. In this study, we planned to repurpose these existing drugs on HCC treatment. We observed a stronger antiproliferative effect of these two combined drugs on HCC cells generated from different etiologies as compared to the single treatment. Global RNA-seq analyses revealed a decrease in the expression of G2/M cell cycle transition genes in HCC cells following combination treatment, suggesting G2 phase cell arrest. We observed G2/M cell cycle phase arrest in HCC cells upon combination treatment compared to the single-treated or vehicle-treated control cells. The downregulation of CCNA2 and CDC25C following combination therapy further supported the observation. Subsequent analyses demonstrated that combination treatment inhibited 70 kDa ribosomal protein S6 kinase (p70S6K) phosphorylation, and increased Bim expression. Apoptosis of HCC cells were accompanied by increased poly (ADP-ribose) polymerase cleavage and caspase-9 activation. Next, we observed that a combination therapy significantly delayed the progression of HCC xenograft growth as compared to vehicle control. Together, our results suggested combining cabozantinib and silmitasertib would be a promising treatment option for HCC.

Anti-Proliferative and Anti-Migratory Activity of Licorice Extract and Glycyrrhetinic Acid on Papillary Thyroid Cancer Cell Cultures

Papillary thyroid cancer (PTC) is the 8th most common cancer among women overall. Licorice contains over 300 active compounds, many of them with anti-cancer properties. Glycyrrhetinic acid (GA) is a major component of licorice. The aim of this study was to investigate the potential anti-proliferative effects of licorice and GA on PTC cell cultures. Licorice extract (LE) was produced from the root and tested on BCPAP and K1 cell lines, as well as GA and aldosterone. We used the MTT test to investigate the anti-proliferative activity, the wound healing test for the migratory activity, and finally, we analyzed cell cycle distribution, apoptosis, and oxidative stress after LE, GA, or aldosterone incubation. Both LE and GA reduced cell viability at 48 h and cell migration at 24 h in both PTC cultures. Aldosterone reduced cell migration only in K1 cells. LE and GA induced cell cycle arrest in the G0/G1 phase in the BCPAP cell line, while LE and aldosterone induced it in the K1 culture. GA but not LE increased the apoptosis rate in both cell lines, whereas LE but not GA increased oxidative stress in both cultures. This study presents the first evidence of the in vitro anti-proliferative and anti-migratory activity of LE and GA on PTC.

Benzoxaborinine, New Chemotype for Carbonic Anhydrase Inhibition: Ex Novo Synthesis, Crystallography, In Silico Studies, and Anti-Melanoma Cell Line Activity.

The benzoxaborinine scaffold, a homologue of benzoxaborole with an additional carbon atom in the boracycle, shows significant potential in developing new therapeutic agents. This study reports the synthesis, inhibition assays against four human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, and anti-melanoma evaluation of 7-aryl(thio)ureido-substituted benzoxaborinines. Some derivatives, particularly compound 11, exhibited potent inhibitory activity (below 65 nM) against hCA IX and XII and stronger antiproliferative effects than SLC-0111 on human melanoma cells under hypoxia. Crystallographic studies of benzoxaborinine 3 adducts with hCA I and II demonstrated the binding mode of this chemotype, revealing that although both benzoxaborinine 3 and benzoxaborole 10 share a similar zinc-binding mode, the expanded ring in benzoxaborinine led to a different orientation within the active site. These findings suggest that benzoxaborinines hold promise for designing novel carbonic anhydrase inhibitors.

Effects of inhaled nitric oxide on endothelial function in patients with ischemic stroke

BACKGROUND: A crucial pathogenetic link in the development of stroke is the deterioration of endothelial function, which is a pathological condition characterized by an imbalance between endothelium-dependent relaxing and constricting factors. An example of an endothelium-dependent relaxing factor is nitric oxide, a substance synthesized by the body’s cells that has a vasodilating, antithrombogenic, anti-inflammatory, and antiproliferative effect. Studies have shown the neuroprotective function of inhaled nitric oxide after ischemia; however, determining the minimum effective dose of inhaled nitric oxide in patients who have suffered an acute cerebrovascular accident remains challenging. AIM: To analyze the protective effect of exogenous nitric oxide using the TIANOX device on the vascular endothelium in patients who have had an ischemic stroke in the early and late recovery period during medical rehabilitation. MATERIALS AND METHODS: The study involved 21 patients (10 people in the main group, 56.9±8.9 years old, 11 people in the control group, 57.2±8.8 years old) in the early or late recovery period after an ischemic stroke. Patients in the main group underwent an individual medical rehabilitation program and a course of 8–10 inhalations of a gas mixture with nitric oxide at 20 ppm for 20 minutes. Those in the control group underwent an individual rehabilitation course without nitric oxide therapy. Flow-dependent vasodilation of the brachial artery was evaluated to assess endothelial function. RESULTS: In the main group, a statistically insignificant (p 0.05) increase was found in the diameter of the brachial artery (3.68±0.64 mm), whereas in the control group, this indicator at rest during repeated diagnostics was less than the initial one (3.09±0.87 mm). During repeated diagnostics, the average endothelial shear velocity in patients of the control group increased from 141.53±52.62 to 159.3±82 versus from 143.17±43.53 to 143.48±46.37 in the main group; however, the results were not statistically significant (p=0.753). CONCLUSION: The increase in the diameter of the brachial artery during flow-dependent vasodilation in patients in the main group may indicate a prosthetic effect of the exogenous form of nitric oxide when using the Tianox device on the vascular endothelium, owing to the possibility of depositing nitric oxide in the body. To confirm the obtained data, a larger sample size of patients is critical in order to further divide the groups of patients into early and late recovery periods after ischemic stroke.

Study of Anti-proliferative Effect and Scratch Wound Migration Assay of Ethanol Extract of <i>Pyrus communis</i> L. Leaf on MCF-7 Model

Objectives: The current aim of the study was twofold: first, to identify the primary phytochemical compounds present in the ethanol extract derived from Pyrus communis L. leaves and second, to assess the extract’s anti-proliferative effect. Materials and Methods: The study conducted an in vitro anti-proliferative investigation of the P. communis leaves extract using the MTT using colorimetric assay against the MCF-7 cell line. These assays collectively provide insights into different aspects of cell behaviour, including proliferation, migration, and invasion, which are important in understanding the overall effect of the extract on the MCF-7 cell line. The protective effect observed in the analysis of the ethanol extract is attributed to the existence of flavonoids and phenols in the extract. Results: Total flavonoid and phenolic contents were observed as 56 mg of quercetin/g and 48 mg of gallic acid/g as standard. This extract ascertained cytotoxic against the MCF-7 cell line in a reverse dose-dependent manner. However, the extract is found to be more potent and effective against MCF-7 (human Breast cancer cell lines) with LC50 value 265.310978μg/ml. Conclusions: The in vitro cytotoxic activity of this extract of the plant leaves has been evaluated, revealing a significant anti-proliferative effect and suppression of cell migration against the MCF-7 cell line. This suggests that the extract may possess compounds or properties that inhibit cell proliferation followed by wound migration, which are crucial factors in cancer progression. This approach is motivated by the observed inhibitory effect of cancer cell proliferation and wound migratory effects of the extract against the MCF-7 cell line, as well as the epidemiological evidence suggesting its anti-carcinogenic potential. This avenue of research holds promise for enhancing the effectiveness of cancer therapy and improving patient outcomes.

Deferasirox's Anti-Chemoresistance and Anti-Metastatic Effect on Non-Small Cell Lung Carcinoma.

Clinically approved iron chelators, originally designed to address iron overload disorders, have emerged as potential anticancer agents. Deferasirox (Def), a tridentate iron chelator, has demonstrated antiproliferative effects in cancer. Background/Objectives: This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). Methods: NSCLC A549 cells were treated with Def to assess cytotoxicity, the effect on nuclear and mitochondrial pathways, and iron-containing proteins and genes to evaluate anti-metastasis and chemoresistance. A lung carcinoma mouse model was used for in vivo studies. Results: Our findings revealed that Def induced cytotoxicity, effectively chelated intracellular iron, and triggered apoptosis through the increase in phosphatidylserine externalization and caspase 3 activity. Additionally, Def caused G0/G1 cell cycle arrest by downregulating the ribonucleotide reductase catalytic subunit. Furthermore, Def perturbed mitochondrial function by promoting the production of reactive oxygen species and the inhibition of glutathione as a measurement of ferroptosis activation. Def demonstrated inhibitory effects on cell migration in scratch assays, which was supported by the upregulation of n-myc downstream-regulated gene 1 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the ABCB1 gene. In vivo experiments using a lung carcinoma mouse model showed that Def treatment did not affect the animal's body weight and showed a significant decrease in tumor growth. Conclusions: This investigation lays the groundwork for unraveling Def action's molecular targets and mechanisms in lung carcinoma, particularly within iron-related pathways, pointing out its anti-metastasis and anti-chemoresistance effect.

RETRACTION: PNU-74654 enhances the antiproliferative effects of 5-FU in breast cancer and antagonizes thrombin-induced cell growth via the Wnt pathway.

F. Rahmani, F. Amerizadeh, S. M. Hassanian, M. Hashemzehi, S.-N. Nasiri, H. Fiuji, G. A. Ferns, M. Khazaei, and A. Avan, "PNU-74654 Enhances the Antiproliferative Effects of 5-FU in Breast Cancer and Antagonizes Thrombin-induced Cell Growth via the Wnt Pathway," Journal of Cellular Physiology 234, no. 8 (2019): 14123-14132, https://doi.org/10.1002/jcp.28104. The above article, published online on 11 January 2019 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Robert Heath; and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by a third party on the data presented in the article. Specifically, image elements in Figure 1c were previously published by the same author group in a different scientific context. Additionally, the panels representing the histological staining corresponding to the "Control" and "5-FU" groups in Figure 3b were found to originate from the same biological sample. Finally, splicing sites have been detected within Figure 6b. The concerns were not satisfactorily addressed by the authors upon request. Accordingly, retraction is warranted as the editors have lost trust in the data presented in the article and in its conclusions. The corresponding author Majid Khazaei disagrees with the decision of retraction. No confirmation was obtained by the remaining co-authors.