Potential Roles and Mechanisms of Curcumin and its Derivatives in the Regulation of Ferroptosis.

Ferroptosis is a recently discovered iron-dependent mode of oxidatively regulated cell death. It is not only associated with a wide range of diseases, but it is also a key component of many signaling pathways. In general, ferroptosis is a double-edged sword. On one hand, it induces nonapoptotic destruction of cancer cells, but on the other, it may lead to organ damage. Therefore, ferroptosis can be drug-targeted as a novel means of therapy. The properties of curcumin have been known for many years. It has a positive impact on the treatment of diseases such as cancer and inflammation. In this review, we focus on the regulation of ferroptosis by curcumin and its derivatives and review the main mechanisms by which curcumin affects ferroptosis. In conclusion, curcumin is a ferroptosis inducer with excellent anticancer efficacy, although it also exhibits organ protective and reparative effects by acting as a ferroptosis inhibitor. The differential regulation of ferroptosis by curcumin may be related to dose and cell type.

Anticancer effects of high-dose extracellular citrate treatment in pancreatic cancer cells under different glucose concentrations.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive solid tumor. Recently, the uptake of extracellular citrate by the sodium-dependent citrate transporter (NaCT), encoded by SLC13A5, has been demonstrated to exert profound effects on cancer cell metabolism. However, research on the function of extracellular citrate in PDAC pathogenesis and the relationship between NaCT expression and the tumor metabolic microenvironment is limited. Therefore, we aimed to evaluate the expression of citrate transporters across a spectrum of glucose concentrations in pancreatic cancer and systematically explore the effects of sodium citrate treatment on pancreatic cancer cells at different glucose concentrations. We observed a positive correlation between glucose concentration and NaCT expression in PDAC cell lines. Extracellular sodium citrate significantly reduced cell viability partially due to reduction in intracellular Ca2+ levels and decreased the migration of human PDAC cells. Furthermore, we observed a decrease in the levels of the stem cell marker prominin I (CD133) following sodium citrate treatment. Notably, the combination treatment of gemcitabine and extracellular sodium citrate exhibited a synergistic anticancer effect in both two-dimensional (2D) and three-dimensional (3D) culture systems. Additionally, we confirmed that pH slightly increased upon administration of sodium citrate, indicating that this could potentially augment the efficacy of gemcitabine. Altogether, these findings suggest that exogenous sodium citrate treatment, particularly in combination with gemcitabine, may represent a novel therapeutic strategy for treating PDAC. This approach holds promise for disrupting PDAC cell metabolism and inhibiting tumor progression.

Combined treatment with Aronia berry extract and oligomeric proanthocyanidins exhibit a synergistic anticancer efficacy through LMNB1-AKT signaling pathways in colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent and highly recurrent malignancies worldwide and currently ranks as the second leading cause of cancer-related deaths. The high degree of morbidity and mortality associated with CRC is primarily attributed to the limited effectiveness of current therapeutic approaches and the emergence of chemoresistance to standard treatment modalities. Recent research indicates that several natural products, including Aronia berry extracts (ABE) and oligomeric proanthocyanidins (OPCs), might offer a safe, cost-effective, and multitargeted adjunctive role to cancer treatment. Herein, we hypothesized a combined treatment with ABE and OPCs could synergistically modulate multiple oncogenic pathways in CRC, thereby enhancing their anticancer activity. We initially conducted a series of in vitro experiments to assess the synergistic anticancer effects of ABE and OPCs on CRC cell lines. We demonstrate that these two compounds exhibited a superior synergistic anticancer potential versus individual treatments in enhancing the ability to inhibit cell viability, suppress colony formation, and induce apoptosis (p < 0.05). Consistent with our in vitro findings, we validated this combinatorial anticancer effect in tumor-derived 3D organoids (PDOs; p < 0.01). Using genome-wide transcriptomic profiling, we identified that a specific gene, LMNB1, associated with the cell apoptosis pathway, was found to play a crucial role in exhibiting anticancer effects with these two products. Furthermore, the combined treatment of ABE and OPCs significantly impacted the expression of key proteins involved in apoptosis, including suppressed expression levels of LMNB1 in CRC cell lines (p < 0.05), which resulted in inhibiting downstream AKT phosphorylation. In conclusion, our study provides novel evidence of the synergistic anticancer effects of ABE and OPCs in CRC cells, partially mediated through the regulation of apoptosis and the oncogene LMNB1 within the AKT signaling pathway. These findings have the potential to better appreciate the anticancer potential of natural products in CRC and help improve treatment outcomes in this malignancy.

Genistein and daidzein induce ferroptosis in MDA-MB-231 cells.

OBJECTIVES: In recent years, there has been a growing interest in targeting ferroptosis for the treatment and prevention of multiple cancers. This study aimed to assess the contribution of ferroptosis to the antiproliferative effects of genistein (GN) and daidzein (DZ) in breast cancer cell lines. METHODS: MDA-MB-231 and MCF-7 cells were employed as an in vitro model. The antiproliferative effects of GN and DZ were determined by WST-1 assay in the presence of specific inhibitors of different cell death pathways. The mRNA expressions of Gpx4 and Fsp-1, the levels of lipid peroxidation, glutathione (GSH)/glutathione disulfide (GSSG) ratio, and intracellular iron ion content were assessed in GN- or DZ-treated cells. RESULTS: GN and DZ were found to cause ferroptotic cell death in MDA-MB-231, as confirmed by the reversal of viability when cells were pretreated with ferrostatin-1. Furthermore, both phytochemicals induced biochemical markers of ferroptosis, including lipid peroxidation and iron ions levels, and decreased GSH/GSSG levels. The mRNA expression levels of the main anti-ferroptotic genes, Gpx4 and Fsp-1, were diminished by the treatment of both phytochemicals. Surprisingly, ferroptosis did not play a role in GN- or DZ-induced cell death in MCF-7 cells. CONCLUSION: Our findings highlight the potential of GN and DZ as ferroptosis inducers in triple-negative breast cancer cells.

Antimigratory Effect of Lipophilic Cations Derived from Gallic and Gentisic Acid and Synergistic Effect with 5-Fluorouracil on Metastatic Colorectal Cancer Cells: A New Synthesis Route.

Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC-such as 5-fluorouracil (5FU)-remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity.

Fungi-Derived Bioactive Compounds as Potential Therapeutic Agents for Pancreatic Cancer: A Systematic Review.

Pancreatic cancer (PC) is one of the tumors with the lowest 5-year survival rate worldwide due to late diagnosis and lack of effective therapy. Because of this, it is necessary to discover new ways of treatment to increase the quality of life of patients. In this context, the secondary metabolites of several fungi have been shown as a possible therapeutic strategy in several types of cancer, such as colorectal cancer, being able to trigger their action through the induction of apoptosis. The objective was to perform a systematic review process to analyze the studies carried out during the last ten years using secondary metabolites derived from fungi as antitumor treatment against PC. After the search process in three databases (PubMed, SCOPUS, and Web of Science) a total of 199 articles were found, with 27 articles finally being included after screening. The results extracted from this systematic review process made it possible to determine the existence of bioactive compounds extracted from fungi that have been effective in in vitro and in vivo conditions and that may be applicable as a possible therapy to avoid drug resistance in PC, one of the major problems of this disease.

Cinnamaldehyde: Pharmacokinetics, anticancer properties and therapeutic potential (Review).

Cancer incidence is increasing globally, presenting a growing public health challenge. While anticancer drugs are crucial in treatment, their limitations, including poor targeting ability and high toxicity, hinder effectiveness and patient safety, requiring relentless scientific research and technological advancements to develop safer and more effective therapeutics. Cinnamaldehyde (CA), an active compound derived from the natural plant cinnamon, has garnered attention in pharmacological research due to its diverse therapeutic applications. CA has potential in treating a wide array of conditions, including cardiovascular diseases, diabetes, inflammatory disorders and various forms of cancer. The present review comprehensively summarizes the physicochemical and pharmacokinetic profiles of CA, and delves into the latest advancements in elucidating its potential mechanisms and targets across various cancer types. CA and its derivatives have antitumor effects, which encompass inhibiting cell proliferation, arresting the cell cycle, inducing apoptosis, limiting cell migration and invasion, and suppressing angiogenesis. Additionally, the present review explores targeted formulations of CA, laying a scientific foundation for further exploration of its implications in cancer prevention and treatment strategies.

Aronia Berry Extract Modulates MYD88/NF-kB/P-Glycoprotein Axis to Overcome Gemcitabine Resistance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor survival rates, primarily due to the limited effectiveness of gemcitabine (Gem)-based chemotherapy, as well as the acquisition of chemotherapeutic resistance. Aronia berry extracts (ABEs), abundant in phenolic constituents, have been recently recognized for their anticancer properties as well as their encouraging potential to help overcome chemoresistance in various cancers. In the present study, we explored ABE's potential to overcome Gem resistance in PDAC and identify specific growth regulatory pathways responsible for its anticancer activity. Through a series of in vitro experiments in gemcitabine-resistant (Gem-R) cells, we elucidated the synergistic interactions between Gem and ABE treatments. Using advanced transcriptomic analysis and network pharmacology, we revealed key molecular pathways linked to chemoresistance and potential therapeutic targets of ABE in Gem-R PDAC cells. Subsequently, the findings from cell culture studies were validated in patient-derived 3D tumor organoids (PDOs). The combination treatment of ABE and Gem demonstrated significant synergism and anticancer effects on cell viability, proliferation, migration, and invasion in Gem-R cells. Transcriptomic analysis revealed a correlation between the NF-Κb signaling pathway and Gem-R (p < 0.05), exhibiting a marked upregulation of MYD88. Additionally, MYD88 exhibited a significant correlation with the overall survival rates in patients with PDAC patients in the TCGA cohort (HR = 1.58, p < 0.05). The MYD88/NF-Κb pathway contributes to chemoresistance by potentially upregulating efflux transporters like P-glycoprotein (P-gp). Our findings revealed that the combined treatment with ABE suppressed the NF-Κb pathway by targeting MYD88 and reducing P-gp expression to overcome Gem resistance. Lastly, the combination therapy proved highly effective in PDOs in reducing both their number and size (p < 0.05). Our study offers previously unrecognized insights into the ability of ABE to overcome Gem resistance in PDAC cells through its targeting of the MYD88/NF-κb/P-gp axis, hence providing a safe and cost-effective adjunctive therapeutic strategy to improve treatment outcomes in PDAC.

Additive Cytotoxic and Colony-Formation Inhibitory Effects of Aspirin and Metformin on PI3KCA-Mutant Colorectal Cancer Cells.

Human malignancies are one of the major health-related issues throughout the world and are anticipated to rise in the future. Despite huge investments made in anticancer drug development, limited success has been obtained and the average number of FDA approvals per year is declining. So, an increasing interest in drug repurposing exists. Metformin (MET) and aspirin (ASP) possess anticancer properties. This work aims to test the effect of these two drugs in combination on colorectal cancer (CRC) cells in vitro. The effects of MET and/or ASP on cell proliferation, viability, migratory ability, anchorage-independent growth ability (colony formation), and nutrient uptake were determined in two (HT-29 and Caco-2) human CRC cell lines. Individually, MET and ASP possessed antiproliferative, cytotoxic, and antimigratory effects and reduced colony formation in HT-29 cells (BRAF- and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PI3KCA)-mutant), although MET did not affect either 3H-deoxy-D-glucose or 14C-butyrate uptake and lactate production, and ASP caused only a small decrease in 14C-butyrate uptake. Moreover, in these cells, the combination of MET and ASP resulted in a tendency to an increase in the cytotoxic effect and in a potentiation of the inhibitory effect on colony formation, although no additive antiproliferative and antimigratory effects, and no effect on nutrient uptake and lactate production were observed. In contrast, MET and ASP, both individually and in combination, were almost devoid of effects on Caco-2 cells (BRAF- and PI3KCA-wild type). We suggest that inhibition of PI3K is the common mechanism involved in the anti-CRC effect of both MET, ASP and their combination and, therefore, that the combination of MET + ASP may especially benefit PI3KCA-mutant CRC cases, which currently have a poor prognostic.

Enhancing the anticancer effect of androgen deprivation therapy by monocarboxylate transporter 1 inhibitor in prostate cancer cells.

BACKGROUND: Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. METHODS: PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. RESULTS: Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. CONCLUSIONS: Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.

Unveiling the experimental proof of the anticancer potential of ginsenoside Rg3 (Review).

Ginsenoside Rg3 (GS-Rg3), a sterol molecule isolated from ginseng, has demonstrated various immunological properties, including inhibition of cancer cell proliferation and metastasis, reversal of drug resistance and enhancement of chemotherapy sensitivity. The recent surge in attention towards GS-Rg3 can be attributed to its potential as an antitumor angiogenesis agent and as a therapeutic candidate for immunotherapy. The development of GS-Rg3 as an agent for these purposes has accelerated research on its mechanisms of action. The present review summarizes recent studies investigating the antitumor activity of GS-Rg3 and its underlying mechanisms, as well as providing essential information for future studies on GS-Rg3.

Anticancer Effects of BRD4 Inhibitor in Epithelial Ovarian Cancer.

Efforts have been made to develop bromodomain inhibitors as cancer treatments. Sub-pathways, particularly in ovarian cancer, affected by bromodomain-containing protein (BRD) remain unclear. This study verified the antitumor effects of a new drug that can overcome OPT-0139-chemoresistance to treat ovarian cancer. A mouse xenograft model of human ovarian cancer cells, SKOV3 and OVCAR3, was used in this study. Cell viability and proliferation were assessed using MTT and ATP assays. Cell cycle arrest and apoptosis were determined using flow cytometry. BRD4 and c-Myc expression and apoptosis-related molecules were detected using RT-PCR and real-time PCR and Western blot. We confirmed the OPT-0139 effect and mechanism of action in epithelial ovarian cancer. OPT-0139 significantly reduced cell viability and proliferation and induced apoptosis and cell cycle arrest. In the mouse xenograft model, significant changes in tumor growth, volume, weight, and BRD4-related gene expression were observed, suggesting the antitumor effects of BRD4 inhibitors. Combination therapy with cisplatin promoted apoptosis and suppressed tumor growth in vitro and in vivo. Our results suggest OPT-0139, a BRD4 inhibitor, as a promising anticancer drug for the treatment of ovarian cancer by inhibiting cell proliferation, decreasing cell viability, arresting cell cycle, and inducing apoptosis.

Anti-breast cancer activity of the essential oil from grapefruit mint (Mentha suaveolens × piperita).

Grapefruit mint (Mentha suaveolens × piperita) is a hybrid, perennial, and aromatic plant widely cultivated all over the world and used in the food, cosmetics, and pharmaceutical industries mostly for its valuable essential oil. Herein, we evaluated the anticancer activity of the grapefruit mint essential oil, cultivated in Iran. For the chemical composition analysis of essential oil, GC-MS was used. MTT assay was utilized for assessing the cytotoxic activity of the essential oil. The type of cell death was determined by annexin V/PI staining. Essential oil effect on the expression of maternally expressed gene 3 (MEG3), a regulatory lncRNA involved in cell growth, proliferation, and metastasis, was studied using qRT-PCR. Linalool (43.9%) and linalool acetate (40.1%) were identified as the dominant compounds of essential oil. Compared with MCF-7, the MDA-MB-231 cells were more sensitive to essential oil (IC50 = 7.6 µg/ml in MCF-7 and 5.9 µg/ml in MDA-MB-231 after 48 h). Essential oil induced cell death by apoptosis. Wound healing scratch assay confirmed the anti-invasive effect of essential oil. In addition, essential oil upregulated the tumor suppressor MEG3 in breast cancer cells. These results provide new insights into grapefruit mint essential oil potential application as an anticancer adjuvant in combination treatments for breast cancer patients.

Anticancer Effect by Combined Treatment of Artemisia annua L. Polyphenols and Docetaxel in DU145 Prostate Cancer Cells and HCT116 Colorectal Cancer Cells.

Docetaxel (DTX), a semi-synthetic analogue of paclitaxel (taxol), is known to exert potent anticancer activity in various cancer cells by suppressing normal microtubule dynamics. In this study, we examined how the anticancer effect of DTX is regulated by polyphenols extracted from Korean Artemisia annua L. (pKAL) in DU145 prostate cancer cells (mutant p53) and HCT116 colorectal cancer cells (wild-type p53). Here, we show that the anticancer effect of DTX was enhanced more significantly by pKAL in HCT116 cells than in DU145 cells via phase-contrast microscopy, CCK-8 assay, Western blot, and flow cytometric analysis of annexin V/propidium iodide-stained cells. Notably, mutant p53 was slightly downregulated by single treatment of pKAL or DTX in DU145 cells, whereas wild-type p53 was significantly upregulated by pKAL or DTX in HCT116 cells. Moreover, the enhanced anticancer effect of DTX by pKAL in HCT116 cells was significantly associated with the suppression of DTX-induced p53 upregulation, increase of DTX-induced phospho-p38, and decrease of DTX-regulated cyclin A, cyclin B1, AKT, caspase-8, PARP1, GM130, NF-κB p65, and LDHA, leading to the increased apoptotic cell death and plasma membrane permeability. Our results suggest that pKAL could effectively improve the anticancer effect of DTX-containing chemotherapy used to treat various cancers expressing wild-type p53.

Methyl Jasmonate-induced Increase in Intracellular Magnesium Promotes Apoptosis in Breast Cancer Cells.

BACKGROUND/AIM: Methyl jasmonate (MeJa) is a botanical stress hormone that serves as a defense mechanism to inhibit growth in stressed plants. It is well known that MeJa exhibits an anticancer effect by reducing intracellular ATP, activating reactive oxygen species (ROS) production, and promoting mitogen-activated protein kinase (MAPK) activity. Presently, no report has been published on MeJa-induced changes in intracellular Mg2+ concentration ([Mg2+]i), and TRPM7 as an Mg2+ transporter in cancer cells. Therefore, this study aimed to investigate the Mg2+ homeostatic changes and apoptotic effects following MeJa treatment using the MCF-7 human breast cancer cell line. MATERIALS AND METHODS: The MTT assay was used to assess the cell viability and half-inhibitory concentration, microscopic two-photon excitation wavelength spectrophotometry was used to measure the [Mg2+]i, a luminescent assay determined intracellular ATP levels, western blot assay measured TRPM7 levels, antioxidant capacities, endoplasmic reticulum (ER) stress, and MAPK signaling pathways, while the fluorescence assay evaluated ROS concentrations and the cell apoptotic index. RESULTS: This study provides evidence that MeJa has an antiapoptotic effect on MCF-7 cells. The increase in [Mg2+]i led to decreased TRPM7 expression, which is related to elevated ROS production, in addition to elevated ER stress and MAPK signaling pathway activity and decreased ATP content. CONCLUSION: The increase in [Mg2+]i leads to decreased TRPM7 expression and may be the epicenter of MeJa-induced apoptotic cell death in MCF-7 cells.

Potential anticancer effect of free and nanoformulated Deferasirox for breast cancer treatment: in-vitro and in-vivo evaluation.

BACKGROUND: Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects. Additionally, BC is recognized as one of the most resistant forms of malignancy to treatment. Consequently, there exists a critical need for innovative therapeutic agents that are both highly effective and exhibit reduced toxicity and side effects for patients. Deferasirox (DFX), an iron-chelating drug approved by the FDA for oral use, emerges as a promising contender in the fight against BC proliferation. DFX, primarily administered orally, is utilized to address chronic iron excess resulting from blood transfusions, and it is the inaugural treatment for chronic iron overload syndrome. However, DFX encounters limitations due to its poor water solubility. AIM: This study aimed at incorporating DFX into lipid nanocapsules (DFX-LNCs) followed by investigating the anticancer effect of the DFX nanoform as compared to free DFX in-vitro and on an orthotopic BC mouse model in-vivo. METHODS: The DFX-LNCs was prepared and imaged using TEM and also characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI) using DLS. Moreover, drug release, cytotoxicity, and anticancer effect were assessed in-vitro, and in-vivo. RESULTS: The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC50 of 4.417 µg/ml and 16.114 µg/ml, respectively, while the plain LNCs didn't show any cytotoxic effect on the 4T1 cell line (IC50 = 122.797 µg/ml). Besides, the apoptotic effect of DFX-LNCs was more pronounced than that of free DFX, as evidenced by Annexin V/PI staining, increased BAX expression, and decreased expression of BcL-2. Moreover, DFX-LNCs showed a superior antitumor effect in-vivo with potent antioxidant and anti-proliferative effects. CONCLUSION: The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment.

Micellar solution of [223Ra]RaCl2: Reaching renal excretion, potent efficacy in osteoblastic osteosarcoma in PDX model, biochemistry alterations and pharmacokinetics.

Despite the successful use of the radiopharmaceutical radium-223 dichloride ([223Ra]RaCl2) for targeted alpha therapy of castration-resistant prostate cancer patients with bone metastases, some short-term side effects, such as diarrhea and vomiting, have been documented, causing patient discomfort. Hence, we prepared a nanosized micellar solution of [223Ra]RaCl2 and evaluated its biodistribution, pharmacokinetics, and induced biochemical changes in healthy mice up to 96 h after intraperitoneal administration as an alternative to overcome the previous limitations. In addition, we evaluated the bone specificity of micellar [223Ra]RaCl2 in patient-derived xenografts in the osteosarcoma model. The biodistribution studies revealed the high bone-targeting properties of the micellar [223Ra]RaCl2. Interestingly, the liver uptake remained significantly low (%ID/g = 0.1-0.02) from 24 to 96 h after administration. In addition, the micellar [223Ra]RaCl2 exhibited a significantly higher uptake in left (%ID/g = 0.85-0.23) and right (%ID/g = 0.76-0.24) kidneys than in small (%ID/g = 0.43-0.06) and large intestines (%ID/g = 0.24-0.09) over time, suggesting its excretion pathway is primarily through the kidneys into the urine, in contrast to the non-micellar [223Ra]RaCl2. The micellar [223Ra]RaCl2 also had low distribution volume (0.055 ± 0.003 L) and longer elimination half-life (28 ± 12 days). This nanosystem was unable to change the enzymatic activities of alanine aminotransferase, aspartate aminotransferase, gamma GT, glucose, and liquiform lipase in the treated mice. Finally, microscopic examination of the animals' osteosarcoma tumors treated with micellar [223Ra]RaCl2 indicated regression of the tumor, with large areas of necrosis. In contrast, in the control group, we observed tumor cellularity and cell anaplasia, mitotic figures and formation of neoplastic extracellular bone matrix, which are typical features of osteosarcoma. Therefore, our findings demonstrated the efficiency and safety of nanosized micellar formulations to minimize the gastrointestinal excretion pathway of the clinical radiopharmaceutical [223Ra]RaCl2, in addition to promoting regression of the osteosarcoma. Further studies must be performed to assess dose-response outcomes and organ/tissue dosimetry for clinical translation.

Enrichment process, structural prediction, isolation, in vitro cytotoxic and anti-inflammatory effects of triterpenoid saponins in Camellia japonica L. leaves water extract through UPLC-Q-TOF based mass spectrometry similarity networking.

Camellia japonica L. is rich in bioactive compounds, but its health-enhancing potential is often overshadowed by its ornamental value. Notably, triterpenoid saponins are prominent due to their surfactant properties. MolNetEnhancer revealed 537 compounds in C. japonica leaves water extract, classified into 32 categories, including 38 triterpenoid saponins. To enrich triterpenoid saponins, the process of D101 resin chromatography was employed. Molecular networking analysis based on UPLC-Q-TOF and quantitative analysis based on HPLC revealed saponins concentrated in fractions 3 and 4 (68.3% transfer). MS2LDA and NAP predicted structures for 38 triterpenoid saponins, revealing nearly half of them are potential new compounds. Comprehensive chromatographic and spectroscopic methods were used for purification and structural illustration of triterpenoid saponins, yielding 13, including 7 new compounds. Statistical analysis and in vitro assays revealed the cytotoxic and anti-inflammatory activities of these triterpenoid saponins played a crucial role in the anticancer effects.

Antiproliferative and anti-inflammatory effects of fractionated crude lectins from boiled kidney beans (Phaseolus vulgaris).

In this study, we investigated the biological profile of lectins isolated from raw and boiled Japanese red Kintoki beans (red kidney beans [RKB]; Phaseolus vulgaris). Lectins in beans showing agglutination activity were retained after heating. Raw and boiled RKB lectins were fractionated using carboxymethyl- and diethylaminoethyl-Sepharose, respectively. Boiled RKB lectins were evaluated for carbohydrate specificity as well as cytokine-inducing and antiproliferative activities against cancer cells and compared with raw RKB lectins. Raw RKB lectins showed specificity for thyroglobulin and fetuin, whereas boiled lectins showed specificity for N-acetylneuraminic acid. Raw RKB lectins showed low resistance to proteases and tolerated temperatures greater than 80°C for 5 min. Notably, lectins from raw and boiled beans showed antiproliferative activity against five types of cancer cells B16, LM8, HeLa, HepG2, and Colo 679. In particular, lectins from raw beans exhibited a significantly stronger activity than those from boiled beans. Anti-inflammatory effects were notably observed in crude extracts from raw and boiled beans. Specifically, lectins fractionated from boiled beans markedly inhibited the expression of tumor necrosis factor-α and interleukin-6. Overall, our results showed that RKB lectins from boiled beans exert anti-inflammatory and anticancer effects and could be developed as potential chemopreventive agents. PRACTICAL APPLICATION: Japanese red kidney beans (RKB) are cultivated in numerous parts of the temperate zone and consumed in many countries. Lectins from boiled beans exhibited anticancer activity, similar to lectins from raw beans. Additionally, crude and fractionated lectins from boiled beans showed anti-inflammatory activity. Thus, boiled RKB lectins have the potential to be used as a bioactive protein for medical research and could be developed as anticancer agents.

Anticancer effect of covalent purine-containing EGFR TKI, ZZC4 and its mechanism of action through network pharmacology.

AIMS: Epidermal growth factor receptor (EGFR) has been documented in many malignancies as participating in the progression of cancer cells. Here, we present a novel EGFR tyrosine kinase inhibitor, ZZC4, and examine its effect on cancer cell proliferation, migration, and tumor-bearing xenograft models. MAIN METHODS: The antiproliferative effect of ZZC4 was assessed in vitro by MTT assay, colony formation, and wound healing assay and in vivo with tumor-bearing xenograft nude mice. Further, Western blotting analysis and computational network pharmacology were used to explore and understand the mechanism of ZZC4. KEY FINDINGS: The results showed that ZZC4 potently inhibited the proliferation of lung, breast, and melanoma cells, and was more sensitive to lung cancer cells HCC827, H1975, and breast cancer cell T47D. In vitro findings were corroborated in vivo as results showed the suppressive effect of ZZC4 on HCC827 and H1975 tumor growth. Western blotting analysis confirmed that ZZC4 is an effective inhibitor of the EGFR pathways as it down-regulated p-EGFR, p-Akt, and p-MAPK. Computational molecular docking confirmed the strong binding affinity between ZZC4 and EGFR. Moreover, network pharmacology suggested that ZZC4 might play a suppressive role in the progression of malignancies with EGFR/PI-3K/Akt axis dysregulation or in cancer-related drug resistance. SIGNIFICANCE: Our study showed that ZZC4 is an anticancer drug candidate.