Anticancer Effects Research Articles

The multifaceted role of beta-blockers in overcoming cancer progression and drug resistance: Extending beyond cardiovascular disorders.

Beta-blockers are commonly used medications that antagonize β-adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta-blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta-adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta-blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta-blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.

Piceatannol induces caspase-dependent apoptosis by modulating intracellular reactive oxygen species/mitochondrial membrane potential and enhances autophagy in neuroblastoma cells.

The aim of this study was to evaluate the anticancer effects of piceatannol, a natural stilbenoid, on human neuroblastoma cells. In order to accomplish this goal, we performed various cellular assays, including the XTT cell proliferation assay for cell viability, colony formation assay for colony formation capacity, FITC Annexin V and cell death detection kit for apoptosis, matrigel invasion assay for invasion capacity, intracellular reactive oxygen species (ROS) red dye for intracellular ROS levels, TMRM staining method for mitochondrial membrane potential (MMP), and the CYTO-ID autophagy detection kit for autophagy. Furthermore, we analyzed the expression levels of genes associated with apoptosis and autophagy using RT-qPCR. Based on our findings, piceatannol exhibited cytotoxic effects on neuroblastoma cells. Besides, treatment with piceatannol at both 50 and 100 μM concentrations for 72 h decreased colony formation, induced apoptosis and autophagy, inhibited cell invasion, decreased MMP, and increased ROS levels in SH-SY5Y cells. In addition, we observed significant upregulation in the expression levels of CASP8, BECLIN, ATG5, ATG7, and MAPILC3A genes between the two doses. These results suggest that piceatannol enhances autophagic activity and induces caspase-dependent apoptosis, indicating its potential as a therapeutic agent against neuroblastoma cells.

The 3,3'-dimethoxy-4,4'-dihydroxy-stilbene Triazole (STT) Inhibits Liver Cancer Cell Growth by Targeting Akt/mTOR Pathway.

The present study was aimed to investigate the proliferation inhibitory ability of 3,3'-dimethoxy-4,4'-dihydroxy-stilbene triazole (STT) on SNU449 and Huh7 cells. Moreover, the mechanism associated with the suppression of liver cancer cell proliferation by STT was also studied. The results revealed that STT suppresses proliferation of SNU449 and Huh7 cells to 28 and 21%, respectively treatment with 20 µM. The clonogenic survival of SNU449 and Huh7 cells was also significantly reduced after incubation with STT compared to the control cultures. In comparison to the control, STT treatment significantly decreased the invasive potential of SNU449 cells. Treatment with STT led to a prominent suppression in p62 and increase in LC3B protein expression in SNU449 cells compared to the control cells. The STT treatment dramatically decreased p-Akt and p-mTOR protein expression in SNU449 cells. Docking study revealed that STT interacts via traditional hydrogen bonding with the glutamine, phenylalanine, leucine, serine, arginine, aspartic acid, and lysine residues of Akt protein. In summary, the current study demonstrates that STT effectively suppresses the viability of SNU449 and Huh7 liver cancer cells. Moreover, STT treatment of the liver cancer cells also significantly reduces the clonogenic survival and invasive potential of SNU449 cells. Treatment of liver cancer cells with STT increases the expression of autophagic, targets anti-autophagic protein expression and down-regulates Akt/mTOR pathway to inhibit cancer growth and proliferation. Thus, STT exhibits prominent anticancer effect and needs to be investigated further as a potential candidate for the treatment of liver cancer.

A biochemical assessment of apoptosis-inducing impact of Salinomycin in combination with ciprofloxacin on human leukemia KG1-a stem-like cells in the presence and absence of insulin.

Acute Myeloid Leukemia (AML) is a fast-developing invading cancer that impacts the blood and bone marrow, marked by the rapid proliferation of abnormal white blood cells. Chemotherapeutic agents, a primary treatment for AML, encounter clinical limitations such as poor solubility and low bioavailability. Previous studies have highlighted antibiotics as effective in inducing cancer cell death and potentially preventing metastasis. Besides, insulin is known to activate the PI3K/Akt pathway, often disrupted in cancers, leading to enhanced cell survival and resistance to apoptosis. In light of the above-mentioned points, we examined the anti-cancer impact of antibiotics Ciprofloxacin (CP) and Salinomycin (SAL) and their combination on KG1-a cells in the presence and absence of insulin. This was accomplished by exposing KG1-a cells to different doses of CP and SAL alone, in combination, and with or without insulin for 24-72h. Cell viability was evaluated using the MTT assay. Besides, apoptotic effects were examined using Hoechst staining and Annexin-V/PI flow cytometry. The expression levels of Bax, p53, BIRC5, Akt, PTEN, and FOXO1 were analyzed through Real-Time PCR. CP and SAL demonstrated cytotoxic and notable pro-apoptotic impact on KG1-a cells by upregulating Bax and p53 and downregulating BIRC5, leading to G0/G1 cell cycle arrest and prevention of the PI3K-Akt signaling pathway. Our findings demonstrated that combination of CP and SAL promote apoptosis in the KG1-a cell line by down-regulating BIRC5 and Akt, as well as up-regulating Bax, p53, PTEN, and FOXO1. Additionally, the findings strongly indicated that insulin effectively mitigates apoptosis by enhancing Akt expression and reducing FOXO1 and PTEN gene expression in the cells treated with CP and SAL. Our findings showed that the combined treatment of CP and SAL exhibit a strong anti-cancer effect on leukemia KG1-a cells. Moreover, it was discovered that the PI3K-Akt signaling can be a promising target in leukemia treatment particularly in hyperinsulinemia condition.

Design, synthesis, and evaluation of benzodioxolane compounds for antitumor activity

This study reports the design, synthesis, and comprehensive biological evaluation of 13 benzodioxolane derivatives, derived from the core structure of piperine, a natural product with established antitumor properties. Piperine, primarily found in black pepper, has been noted for its diverse pharmacological activities, including anti-inflammatory, antioxidant, and anticancer effects. Leveraging piperine’s antitumor potential, we aimed to enhance its efficacy through structural modifications. Among the synthesized compounds, HJ1 emerged as the most potent, exhibiting a 4-fold and 10-fold increase in inhibitory effects on HeLa and MDA-MB-231 cell lines, respectively, compared to piperine. Furthermore, HJ1 demonstrated a favorable safety profile, characterized by significantly lower cytotoxicity towards the human normal cell line 293T. Mechanistic investigations revealed that HJ1 markedly inhibited clonogenicity, migration, and adhesion of HeLa cells. In vivo studies utilizing the chick embryo chorioallantoic membrane (CAM) model substantiated the robust antitumor activity of HJ1, evidenced by its ability to suppress tumor angiogenesis and reduce tumor weight. These results suggest that HJ1 holds significant promise as a lead compound for the development of novel antitumor therapies.

Polyunsaturated Fatty Acids in Quinoa Induce Ferroptosis of Colon Cancer by Suppressing Stemness.

Polyunsaturated fatty acids (PUFAs) are essential nutrients for the human body, playing crucial roles in reducing blood lipids, anti-inflammatory responses, and anticancer effect. Quinoa is a nutritionally sound food source, rich in PUFAs. This study investigates the role of quinoa polyunsaturated fatty acids (QPAs) on quelling drug resistance in colorectal cancer. The results reveal that QPA downregulates the expression of drug-resistant proteins P-gp, MRP1, and BCRP, thereby enhancing the sensitivity of colorectal cancer drug-resistant cells to the chemotherapy drug. QPA also inhibits the stemness of drug-resistant colorectal cancer cells by reducing the expression of the stemness marker CD44. Consequently, it suppresses the downstream protein SLC7A11 and leads to ferroptosis. Additionally, QPA makes the expression of ferritin lower and increases the concentration of free iron ions within cells, leading to ferroptosis. Overall, QPA has the dual-function reversing drug resistance in colorectal cancer by simultaneously inhibiting stemness and inducing ferroptosis. This study provides a new option for chemotherapy sensitizers and establishes a theoretical foundation for the development and utilization of quinoa.

Transforming Albumin into a Trojan Horse of Immunotherapy-Resistant Colorectal Cancer with a High Microsatellite Instability.

The therapeutic response of microsatellite instability-high (MSI-H) colorectal cancer (CRC) to immune checkpoint inhibitors (ICI) is indeed surprising; however, the emergence of acquired resistance poses an even greater threat to the survival of these patients. Herein, bioinformatics analysis of MSI-H CRC samples revealed that Wnt signaling pathway represents a promising target for acquired immune reactivation, while subsequent analysis and biochemical testing substantiated the inclination of Wnt-hyperactive CRC cells to engage in macropinocytosis with human serum albumin (HSA). These findings have inspired us to develop an engineered HSA that not only possesses the ability to specifically target cancer cells but also effectively suppresses the Wnt/β-catenin cascade within these malignant cells. In pursuit of this objective, a comprehensive screening of reported Wnt small-molecule inhibitors was conducted to evaluate their affinity with HSA, and it was discovered that Carnosic acid (CA) exhibited the highest affinity while simultaneously revealing multiple binding sites. Further investigation revealed that CA HSA the capability to engineer HSA into spherical and size-tunable nanostructures known as eHSA (Engineering HSA particle), which demonstrated optimized macropinocytosis-dependent cellular internalization. As anticipated, eHSA effectively suppressed the Wnt signaling pathway and reactivated the acquired immune response in vivo. Furthermore, eHSA successfully restored sensitivity to Anti-PD1's anticancer effects in both subcutaneous and orthotopic mouse homograft models of MSI-H CRC, as well as a humanized hu-PBMC patient-derived orthotopic xenograft (PDOX) mouse model of MSI-H CRC, all while maintaining a favorable safety profile. The collective implementation of this clinically viable immune reactivation strategy not only enables the delivery of Wnt inhibitors for CRC therapy, but also serves as an exemplary demonstration of precision-medicine-guided nanopharmaceutical development that effectively harnesses specific cellular indications in pathological states.

Protein hydrolysates of millets: an effective therapeutic to wide range of diseases

Purpose Millets are underused crops that have the potential to withstand harsh environmental conditions. Recent research has proved immense nutritional benefits associated with millets which have increased their utilization to some extent but yet their sole potential is left to be exploited. Different millet varieties have exceptional nutritional and nutraceutical properties which can ameliorate even the deadly conditions of cancers. They have significant protein composition ranging from 10% to 12% which possess effective bioactive potential. Protein hydrolysates containing bioactive peptides have been evaluated for their therapeutic effects against a variety of diseases. This review aims to discuss the bioactive potential of different millet protein hydrolysates to encourage research for development of effective natural therapeutics. Design/methodology/approach The present article elaborates on effective studies on the therapeutic effects of millet protein hydrolysates. Findings Several effective millet peptides have been reported for their therapeutic effect against different diseases and their antioxidant, anti-inflammatory, anticancer, antimicrobial and antidiabetic effects have been investigated. Originality/value This review focuses on millet bioactive peptides and their significance in treating variety of diseases. Thus, will further encourage research to explore the novel therapeutic effects of millet proteins hydrolysates which can eventually result in the development of natural and safe therapeutics.

Anlotinib destabilizes PAX3-FOXO1 to induce rhabdomyosarcoma cell death via upregulating NEK2

BackgroundRhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children and adolescents, in which PAX3-FOXO1 fusion gene positive patients have very poor prognosis. PAX3-FOXO1 has been identified as an independent prognostic predictor in RMS, with no currently available targeted therapeutic intervention. The novel tyrosine kinase inhibitor anlotinib exhibits a wide range of anticancer effects in multiple types of cancers; however, there have been no relevant studies regarding its application in RMS. Materials and methodsWe investigated the effects of PAX3-FOXO1 on the therapeutic efficacy of anlotinib using the CCK-8 assay, flow cytometry, invasion assay, wound healing assay, western blotting, quantitative polymerase chain reaction(qPCR), and xenograft experiments. RNA-seq and co-immunoprecipitation assays were conducted to determine the specific mechanism by which anlotinib regulates PAX3-FOXO1 expression. ResultsAnlotinib effectively inhibited RMS cell proliferation and promoted apoptosis and G2/M phase arrest while impeding tumor growth in vivo. Downregulation of PAX3-FOXO1 enhances the antitumor effects of anlotinib. Anlotinib upregulates protein kinase NEK2 and increases the degradation of PAX3-FOXO1 via the ubiquitin-proteasome pathway, leading to a reduction in PAX3-FOXO1 protein levels. ConclusionAnlotinib effectively inhibited the malignant progression of RMS and promoted degradation of the fusion protein PAX3-FOXO1. Anlotinib could be a targeted therapeutic approach to treat PAX3-FOXO1 fusion-positive RMS.

Chrysin Enhances Anti-cancer Activity of Jurkat T Cell and NK-92 Cells Against Human Breast Cancer Cell Lines.

Chrysin, a naturally occurring flavonoid in plant and bee products, demonstrates notable biological activities, including anti-cancer effects. These properties are partially attributed to its capability to activate immune cells. This study focused on exploring the immunomodulatory potential of chrysin on NK-92 and Jurkat-T cells targeting breast cancer cells (BCC). Chrysin leads to activation of NK-92 and T cells facilitated by the addition of human recombinant IL-2 and PHA-M. The anti-cancer efficacy of chrysin on these immune cells was evaluated in a co-culture setup with EGF-stimulated MCF-7 and MDA-MB-231 cells. Findings revealed that chrysin notably increased the cytotoxicity of NK-92 and T cells towards MCF-7 and MDA-MB-231 cells, with the most significant impact observed on MCF-7 cells (20%). The activation of NK-92 cells, marked by increased IFN-γ production and CD56 expression, correlated with enhanced secretion of cytokines. Additionally, the activation of these cells against BCC was linked with elevated levels of granzyme-B, TNF-α, and nitric oxide (NO). Similarly, the cytotoxic activation of Jurkat-T cells against BCC was characterized by increased production of granzyme-B, IL-2, and IFN-γ. Consequently, these results support the hypothesis that chrysin significantly contributes to the activation and functional enhancement of NK-92 and T-cells against two distinct BCC lines.

Two spurge species, Euphorbia resinifera O. Berg and Euphorbia officinarum subsp. echinus (Hook.f. & Coss.) Vindt inhibit colon cancer

BackgroundColon cancer, a prominent contributor to global cancer-related deaths, prompts the need for innovative treatment strategies. Euphorbia resinifera O. Berg (E. resinifera) and Euphorbia officinarum subsp. echinus Hook. f. & Coss Vindt (E. echinus) and their bee-derived products have been integral to traditional Moroccan medicine due to their potential health benefits. These plants have historical use in addressing various health issues, including cancer. However, their effects against colon cancer remain unclear, and the specific mechanisms underlying their anti-cancer effects lack comprehensive investigation.MethodsThe study aimed to assess the potential anti-cancer effects of Euphorbia extract on colon cancer cell lines (DLD-1) through various techniques. The apoptosis, migration, and proliferation of DLD-1 cells were measured in DLD-1 cells. In addition, we conducted High-Performance Liquid Chromatography (HPLC) analysis to identify the profile of phenolic compounds present in the studied extracts.ResultsThe extracts demonstrated inhibition of colon cancer cell migration. E. resinifera flower and E. echinus stem extracts show significant anti-migratory effects. Regarding anti-proliferative activity, E. resinifera flower extract hindered proliferation, whereas E. echinus flower extract exhibited dose-dependent inhibition. Apoptosis assays revealed E. resinifera flower extract inducing early-stage apoptosis and E. echinus flower extract promoting late-stage apoptosis. While apoptotic protein expression indicated, E. resinifera stem and propolis extracts had minimal impact on apoptosis.ConclusionThe findings provide evidence supporting the beneficial effects of E resinifera and E. echinus extracts on colon cancer and exerting anti-cancer properties.

Clerodendrum trichotomum Thunberg—An Ornamental Shrub with Medical Properties

Harlequin glory bower (Clerodendrum trichotomum) is a shrub or small tree belonging to the Lamiaceae family, native to Japan, Korea, and eastern China. It has esthetic value and in Europe, it is cultivated as an ornamental plant. Its sweet-smelling flowers have a white or pink crown. The calyx turns from green to pink–purple over time, providing an especially decorative touch around surrounding the ripe deep-blue fruits that persist until winter. In the areas of its natural occurrence, the leaves and young shoots of C. trichotomum, and sometimes the roots, flowers and fruits, are used in folk medicine due to its anti-inflammatory, analgesic, anticancer, sedative, and hypotensive effects. Products based on Harlequin glory are also used in the treatment of rheumatoid arthritis, joint pain, skin inflammation, or asthma. Preliminary research on the composition of raw material suggests that its health-promoting effect is associated with the presence of numerous secondary metabolites, including phenylpropanoids, flavonoids, lignans, terpenoids, steroids, alkaloids, and anthraquinones. This work reviews the current state of knowledge about the phytochemistry and in vitro and in vivo pharmacological properties of the extracts and main active components isolated from C. trichotomum. It also indicates that before it can be used in modern medicine, further research is necessary regarding the safety and efficacy of the raw material, its mechanisms of action, and dosage.

A clinically compatible in vitro drug-screening platform identifies therapeutic vulnerabilities in primary cultures of brain metastases.

Brain metastases represent the most common intracranial tumors in adults and are associated with a poor prognosis. We used a personalized in vitro drug screening approach to characterize individual therapeutic vulnerabilities in brain metastases. Short-term cultures of cancer cells isolated from brain metastasis patients were molecularly characterized using next-generation sequencing and functionally evaluated using high-throughput in vitro drug screening to characterize pharmacological treatment sensitivities. Next-generation sequencing identified matched genetic alterations in brain metastasis tissue samples and corresponding short-term cultures, suggesting that short-term cultures of brain metastases are suitable models for recapitulating the genetic profile of brain metastases that may determine their sensitivity to anti-cancer drugs. Employing a high-throughput in vitro drug screening platform, we successfully screened the cultures of five brain metastases for response to 267 anticancer compounds and related drug response to genetic data. Among others, we found that targeted treatment with JAK3, HER2, or FGFR3 inhibitors showed anti-cancer effects in individual brain metastasis cultures. Our preclinical study provides a proof-of-concept for combining molecular profiling with in vitro drug screening for predictive evaluation of therapeutic vulnerabilities in brain metastasis patients. This approach could advance the use of patient-derived cancer cells in clinical practice and might eventually facilitate decision-making for personalized drug treatment.

Bio-valorization of Secondary Metabolites Produced by Actinobacterium SRV02, Isolated from Shell Waste Environment Combats Clinical Bacterial Pathogens and Ameliorates Anticancer Effects Against Lung Cancer Cells

Bio-valorization of Secondary Metabolites Produced by Actinobacterium SRV02, Isolated from Shell Waste Environment Combats Clinical Bacterial Pathogens and Ameliorates Anticancer Effects Against Lung Cancer Cells

Resveratrol Inhibits Nasopharyngeal Carcinoma (NPC) by Targeting the MAPK Signaling Pathway.

With conventional cancer treatments facing limitations, interest in plant-derived natural products as potential alternatives is increasing. Although resveratrol has demonstrated antitumor effects in various cancers, its impact and mechanism on nasopharyngeal carcinoma remain unclear. This study aimed to systematically investigate the anti-cancer effects of resveratrol on nasopharyngeal carcinoma using a combination of experimental pharmacology, network pharmacology, and molecular docking approaches. CCK-8, scratch wound, and transwell assays were employed to confirm the inhibitory effect of resveratrol on the proliferation, migration, and invasion of nasopharyngeal carcinoma cells. H&E and TUNEL stainings were used to observe the morphological changes and apoptosis status of resveratrol-treated cells. The underlying mechanisms were elucidated using a network pharmacology approach. Immunohistochemistry and Western blotting were utilized to validate key signaling pathways. Resveratrol inhibited the proliferation, invasion, and migration of nasopharyngeal carcinoma cells, ultimately inducing apoptosis in a time- and dose-dependent manner. Network pharmacology analysis revealed that resveratrol may exert its anti-nasopharyngeal carcinoma effect mainly through the MAPK pathway. Immunohistochemistry results from clinical cases showed MAPK signaling activation in nasopharyngeal carcinoma tissues compared to adjacent tissues. Western blotting validated the targeting effect of resveratrol, demonstrating significant inhibition of the MAPK signaling pathway. Furthermore, molecular docking supported its multi-target role with MAPK, TP53, PIK3CA, SRC, etc. Conclusion: Resveratrol has shown promising potential in inhibiting human nasopharyngeal carcinoma cells by primarily targeting the MAPK pathway. These findings position resveratrol as a potential therapeutic agent for nasopharyngeal carcinoma.

Cardiovascular safety of pimitespib in patients with advanced solid tumors: An open-label, nonrandomized, phase 1 study.

Pimitespib (TAS-116), a first-in-class, oral, selective heat-shock protein 90 inhibitor, is approved as fourth-line treatment for gastrointestinal stromal tumors in Japan. This phase 1 study evaluated the cardiac safety of pimitespib. In this open-label, nonrandomized, multicenter study, Japanese patients (aged ≥20 years) with refractory, advanced solid tumors received placebo on day -1, then pimitespib 160 mg daily on days 1-5 of the cardiac safety evaluation period. Electrocardiograms were conducted at baseline, and on days -2, -1, 1, and 5; and blood samples were collected on days 1 and 5. Patients then received once-daily pimitespib for 5 days every 3 weeks. The primary end point was the time-matched difference in QT interval corrected for heart rate using the Fridericia correction (QTcF) between pimitespib and placebo. Pharmacokinetics, safety, and preliminary efficacy were also assessed. Of the 22 patients in the cardiac safety-evaluable population, no clinically relevant QTc prolongation was observed; the upper bound of the one-sided 95% confidence interval for the time-matched difference in change from baseline in QTcF was <20 msec at all time points on days 1 and 5. Pimitespib pharmacokinetic parameters were consistent with previous data, and the time-matched difference in change from baseline in QTcF showed no marked increase as plasma concentrations increased. The safety profile was acceptable; 40% of patients experienced grade 3 or greater adverse drug reactions, mostly diarrhea (20%). The median progression-free survival was 3.1 months. In Japanese patients with refractory, advanced solid tumors, pimitespib was not associated with clinically relevant QTc prolongation, and there were no cardiovascular safety concerns. Pimitespib is a new anticancer drug that is being used to treat cancer in the stomach or intestines (gastrointestinal stromal tumors). This study demonstrated that pimitespib had no marked effect on heart rhythm or negative effects on the heart or blood vessels and had promising anticancer effects in Japanese patients with advanced solid tumors who were unable to tolerate or benefit from standard treatment.

Therapeutic effect of Nepenthes kampotiana Lecomte ethanol extract (Nk-EE) on androgenic alopecia through the inhibition of apoptosis and 5α-reductase activity

There is increasing interest in hair loss treatment because a growing number of people affected. Nepenthes kampotiana Lecomte is known for its anticancer effects, but its potential for preventing hair loss has not been researched. Therefore, this study focused on the hair loss prevention effects of N. kampotiana Lecomte ethanol extract (Nk-EE). The results showed that Nk-EE had a proliferative effect on human follicle dermal papilla cells and inhibited cell death. In vivo experiments using androgenic areata models showed that Nk-EE had a positive effect on a variety of biomarkers such as hair-to-skin ratio, hair type frequency, and hair thickness. The results of this study suggest that Nk-EE has potential as an effective treatment for androgenic alopecia.

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 &lt; 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 &lt; 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 &lt; 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.

Metallothionein: A Comprehensive Review of Its Classification, Structure, Biological Functions, and Applications

Metallothionein is a cysteine-rich protein with a high metal content that is widely found in nature. In addition to heavy metal detoxification, metallothionein is well known as a potent antioxidant. The high sulfhydryl content of metallothionein confers excellent antioxidant activity, enabling it to effectively scavenge free radicals and mitigate oxidative stress damage. In addition, metallothionein can play a neuroprotective role by alleviating oxidative damage in nerve cells, have an anticancer effect by enhancing the ability of normal cells to resist unfavorable conditions through its antioxidant function, and reduce inflammation by scavenging reactive oxygen species. Due to its diverse biological functions, metallothionein has a broad potential for application in alleviating environmental heavy metal pollution, predicting and diagnosing diseases, and developing skin care products and health foods. This review summarizes the recent advances in the classification, structure, biological functions, and applications of metallothionein, focusing on its powerful antioxidant effects and related functions.

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 &lt; 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 &lt; 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 &lt; 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.