Anticancer Research Articles

Differential cardiac impacts of hematological malignancies and solid tumors: a histopathological and biomarker study

BackgroundCancer patients are known to be associated with increased risk of cardiovascular disease. However, no studies have examined the differential impact of hematologic malignancies (HMs) and solid tumors (STs) on cardiac morphology at the tissue level.ObjectiveWe aimed to examine histopathological features alongside cardiovascular biomarkers in patients with HMs and STs who underwent post-mortem evaluation.MethodsWe analyzed cardiac changes in 198 patients with HMs and 164 patients with solid tumors STs. We compared demographics, echocardiogram data, exposure to various antineoplastic agents, and post-mortem findings. Additionally, cardiac histological validation was conducted on post-mortem cardiac specimens to examine cardiac tissue morphology, focusing on cardiomyocyte nuclear density, collagen content, and collagen fiber orientation.ResultsHM patients displayed significantly disordered collagen fiber alignment (0.71 vs 0.83, P = 0.027), and reduced cardiomyocyte nuclear density (56 vs 72, P = 0.002) compared to ST patients. Similarly, hemoglobin level was decreased (6.71 vs 8.06, P < 0.001) in HM patients compared to ST patients. HM patients also showed elevated B-type natriuretic peptide levels (2,275 vs 867, P < 0.001), without significant differences in creatine-kinase MB and cardiac troponin levels. Multivariate analysis identified increased right ventricular thickness, low diastolic blood pressure, and high cardiac troponin levels as risk factors for cardiac death in HM patients.ConclusionsThis study demonstrates that HM patients have fewer cardiomyocyte nuclei and poorly aligned collagen, with serum biomarker evidence of increased cardiac dysfunction. This supports the necessity for specialized cardiac care for these patients.

Luteolin induces oxidative stress and apoptosis via dysregulating the cytoprotective Nrf2-Keap1-Cul3 redox signaling in metastatic castration-resistant prostate cancer cells.

The treatment of metastatic castration-resistant prostate cancer (mCRPC) is still challenging clinically. Due to the refractor and highly metastatic phenotype of mCRPC, novel therapy strategies need to be investigated. Luteolin, a promising anticancer agent with various biological targets in many cancer types, also has a pro-oxidant effect that selectively triggers ROS and apoptosis. In recent years, among its ROS-mediated mechanisms, the inhibitory effect of luteolin on the nuclear factor-E2-related factor 2 (Nrf2), the main ROS scavenger protein in cancer cells, has been reported. However, no evidence exists that luteolin potentially regulates the Nrf2 or its regulator signaling pathway, Nrf2-Keap1-Cul3 axis, concerning its pro-oxidant effects associated with ROS-triggered apoptosis in any PCa cells or tumor model. In the present study, we investigated for the first time whether the anticancer effect of luteolin is associated with pro-oxidant activity via the regulation of the Nrf2-Keap1-Cul3 redox signaling in PC3 and DU145 mCRPC cells. The results showed that luteolin significantly caused more cytotoxic, apoptotic, and pro-oxidant effects in a dose-dependent manner in mCRPC cells than in WPMY-1 normal prostate fibroblast cells for 72 h. Moreover, significant inhibition of Nrf2-Keap1-Cul3 redox signaling has occurred in response to increasing doses of luteolin in mCRPC cells. The current study put forth the potential pro-oxidant inhibitory effect of luteolin on the Nrf2-Keap1-Cul3 axis in mCRPC cells for the first time. Thus, luteolin might be an attractive therapy strategy with an inhibitory effect on the cytoprotective Nrf2-Keap1-Cul3 redox signaling for treating mCRPC.

Transferrin Protein Corona-Targeted Codelivery of Tirapazamine and IR820 Facilitates Efficient PDT-Induced Hypoxic Chemotherapy on 4T1 Breast Cancer.

Protein corona (PC) formation confers novel biological properties to the original nanomaterial, impeding its uptake and targeting efficacy in cells and tissues. Although many studies discussing PC formation have focused on inert proteins that may inhibit the function of nanomaterials, some functional plasma proteins with intrinsic targeting capabilities can also be adsorbed to the surface of nanomaterials, with active ligand properties to improve the targeting ability. In this approach, nanomaterials are surface-engineered to promote the adsorption of specific functional plasma proteins that are directly targeted to transport nanomaterials to the target site. In this study, T10 peptide-modified liposomes were employed to construct an in situ transferrin (Tf) PC-mediated liposome carrying a hypoxia-sensitive chemotherapy drug (tirapazamine, TPZ) and a photosensitizer (indocyanine green, IR820). The water-soluble drug TPZ was encapsulated in mesoporous silica nanoparticles (MSNs) and coated with IR820 (IR)-loaded liposome. Lipid-coated MSNs can inhibit aggregation in the body and significantly reduce the rapid release of water-soluble drugs, resulting in improved system stability and sustained release. Upon entering the in vivo circulation, T10 bound specifically to Tf in plasma to form an in situ Tf liposome-PC complex with enhanced targeting efficacy compared to traditional ligand-modified active-targeting strategies. However, large-sized PC particles faced challenges in penetrating deep into tumor tissues. IR could kill tumors through photodynamic therapy (PDT) and elicit complementary antitumor effects with the hypoxia-sensitive drug TPZ. This study demonstrates the novel design of in situ PC-mediated multifunctional liposomes for hypoxia-activated chemotherapy combined with PDT, a promising approach to cancer therapy.

In Silico and In Vitro Verification of the Effects of Chemotherapeutic Doxorubicin and 5-Fluorouracil in Combination With Curcumin and Vitamin C on MCF-7 Cells.

Breast cancer ranks among the most prevalent cancers. Enhancing the effectiveness of chemotherapy and patient survival is the objective of many studies. In the literature, no study has investigated the combined effect of vitamin c and curcumin with chemotherapy drugs on cell viability in the MCF-7 cell line, nor the mechanism of inflammation induced by cancer drugs, both in vitro and in silico. Thus, the purpose of this study was to assess the synergistic effect of curcumin and vitamin c in combination with the chemotherapy drugs 5-fluorouracil and doxorubicin. The cytokine hub genes of the Toll-like receptor pathway for the administered drugs were identified using the Cytoscape program, and docking studies were conducted via the Cb Dock2 website. In silico analyses indicated that doxorubicin and curcumin displayed comparable characteristics, achieving the highest interaction scores (-10) with marker proteins, whereas 5-fluorouracil and vitamin c showed lower interaction scores. Cell viability was evaluated through MTT analysis and AO/PI staining, while the expression of inflammation-related markers IL-6, IL-10, and TNF-α proteins determined using the ELISA method. After 24 h, the cell viability of the chemotherapeutic drugs administered in combination with curcumin decreased by up to 28%. Subsequently, applications at 48 and 72 h were performed. These results indicate that the effect of curcumin on cell viability is significant when combined with chemotherapy drugs. In the ELISA test, a 52% expression of IL-6 was noted in MCF-7 cells treated with curcumin, whereas the IL-6 level decreased to 15% in the other experimental groups. An increase was observed in the TNF-α expression with 5-fluorouracil and doxorubicin compared to the control, while a notable decrease was recorded in the applications with vitamin c and curcumin (p < 0.05). This study demonstrates that vitamin c and curcumin exhibit a synergistic effect with chemotherapeutic agents in the inflammatory system.

Albumin nanoparticles-mediated doxorubicin delivery enhances the anti-tumor efficiency in ovarian cancer cells through controlled release.

Doxorubicin (DOX) is an anthracycline commonly used as a first-line treatment option for various malignancies, either as a stand-alone treatment or in combination with other chemotherapeutic agents. However, its efficacy in advanced cancer stages requires high doses, resulting in significant cytotoxicity to normal cells and severe side effects. Nanotechnology offers a promising strategy to mitigate these drawbacks through controlled drug release. In this study, bovine serum albumin nanoparticles (BSA-NPs) were synthesized via the desolvation method and successfully loaded with DOX (DOX-BSA-NPs). Characterization using dynamic light scattering, scanning electron microscopy, Fourier-transform infrared spectroscopy, UV-visible spectroscopy, and high-performance liquid chromatography confirmed efficient drug loading. In vitro studies demonstrated that DOX-BSA-NPs enabled sustained drug release and enhanced intracellular delivery. After treatment with DOX-BSA-NPs, ovarian cancer cells showed a twofold increase in cytotoxicity compared to free DOX. Scratch assays further revealed a significant reduction in cancer cell migration and invasion. Additionally, LDH assays and Annexin V-FITC flow cytometry indicated a shift toward apoptosis over necrosis, enhancing the anti-tumor efficacy of DOX. This was supported by increased reactive oxygen species production, upregulation of pro-apoptotic genes, downregulation of anti-apoptotic genes, and elevated caspase 3 and 7 activity, collectively promoting apoptosis. These findings underscore the potential of DOX-BSA-NPs as a superior alternative for targeted and controlled drug delivery, offering enhanced therapeutic efficacy and reduced side effects in ovarian cancer treatment.

Rhodium complex [RhLI2]I: a novel anticancer agent inducing tumor inhibition and apoptosis

Numerous chemotherapeutic agents are currently employed in cancer treatment, but many are associated with significant side effects. This study aims to identify a novel anticancer drug that minimizes or eliminates these adverse effects. The anticancer activity of the Rhodium (III) complex cis-[RhLI2]I was evaluated through both in vivo and in vitro functional assays. Apoptosis in cancer cells post-treatment was assessed using microscopy and gene expression analysis. In cytotoxicity screening via the brine shrimp lethality bioassay, the compound exhibited an LC50 value of 25.90 µg/mL (P < 0.001). It also achieved an 88.96% inhibition of cell growth (P < 0.001), an 82.39% increase in lifespan (P < 0.001), and a significant reduction in tumor weight at a dosage of 200 µg/kg in Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. Restoration of hematological parameters, such as RBC, WBC, and hemoglobin levels, was observed in treated tumor-bearing mice compared to untreated EAC-bearing mice. The compound inhibited the growth and proliferation of breast cancer (MCF7) cells in a dose-dependent manner, achieving a maximum inhibition of 88.9% at 200 µg/mL. Apoptotic induction in MCF7 cells occurred through the upregulation of p53, Bax, caspase-3, -8, and -9, alongside the downregulation of the anti-apoptotic protein Bcl-2. No long-term adverse effects on hematological or biochemical parameters or tissue levels were observed in the mice. Given these findings, this compound demonstrates significant cytotoxic effects and has the potential to serve as a promising chemotherapeutic agent, warranting further investigation at more advanced stages.

Cationic Micelle-like Nanoparticles as the Carrier of Methotrexate for Glioblastoma Treatment

In the present study, ultra-small, magnetic, oleyl amine-coated Fe3O4 nanoparticles were synthesized and stabilized with a cationic ligand, cetyltrimethylammonium bromide, and an anticancer drug, methotrexate, was incorporated into a micelle-like nanoparticle structure for glioblastoma treatment. Nanoparticles were further characterized for their physicochemical properties using spectroscopic methods. Drug incorporation efficiency, drug loading, and drug release profile of the nanoparticles were investigated. According to the results, max incorporation efficiency% of 89.5 was found for 25 µg/mL of methotrexate-loaded nanoparticles. The cumulative amount of methotrexate released reached 40% at physiological pH and 85% at a pH of 5.0 up to 12 h. The toxicity and anticancer efficacy of the nanoparticles were also studied on U87 cancer and L929 cells. IC50 concentration of nanoparticles reduced cell viability to 49% in U87 and 72% in L929 cells. The cellular uptake of nanoparticles was found to be 1.92-fold higher in U87 than in L929 cells. The total apoptosis% in U87 cells was estimated to be ~10-fold higher than what was observed in the L929 cells. Nanoparticles also inhibited the cell motility and prevented the metastasis of U87 cell lines. Overall, designed nanoparticles are a promising controlled delivery system for methotrexate to the cancer cells to achieve better therapeutic outcomes.

Assessing the continuum of care in Sub-Saharan African hospitals performing surgery for breast cancer: a secondary analysis of the GlobalSurg 3 study

BackgroundWhile breast cancer incidence rates in Sub-Saharan Africa (SSA) are among the lowest worldwide, mortality rates remain among the highest, reflecting particularly poor survival. Only a few studies in SSA have investigated the capabilities of treatment services to adequately provide a continuum of care for breast cancer. Our aim was to assess the availability of diagnostic facilities and adjuvant therapies in hospitals performing breast cancer surgery in SSA.MethodsWe performed a secondary analysis of the GlobalSurg3 study data collected in the SSA region. The GlobalSurg 3 study is a multicenter, international, prospective, observational study of hospitals providing surgical services for cancer patients (including breast cancer) around the world. A total of 47 hospitals from 15 SSA countries and 43 cities were included between April 1, 2018, and Jan 31, 2019.ResultsOne-third of hospitals covered a population greater than two million (n = 17; 36.2%). Ultrasound was available in all hospitals; however, it was not consistently functional in 11 hospitals (23.4%). Only half of the included hospitals (n = 26, 55.3%) had access to a full-time pathologist, whilst the multidisciplinary team (MDT) approach was absent in 42.4% of hospitals. Radiotherapy equipment was only available in nine hospitals (19.1%). Only half of the hospitals (n = 25, 53.1%) had chemotherapy drugs available on site. In nine hospitals (19.1%), patients had to travel more than 50 km to access chemotherapy drugs.ConclusionsOutcomes for breast cancer patients in SSA cannot be improved without significant investments in pathology, surgical and oncological treatment pathways to provide timely diagnostic and effective treatment.

Molecular modeling, synthesis and biological evaluation of caffeic acid based Dihydrofolate reductase inhibitors

Dihydrofolate reductase (DHFR) is an enzyme that plays a crucial role in folate metabolism, which is essential for cell growth and division. DHFR has been identified as a molecular target for numerous diseases due to its significance in various biological processes. DHFR inhibitors can disrupt folate metabolism by inhibiting DHFR, leading to the inhibition of cell growth. So, a series of caffeic acid derivatives were designed, synthesized, characterized and evaluated for their in vitro ability to inhibit DHFR, as well as their antimicrobial and anticancer properties. Among all synthesized compounds, compound CE11 exhibited the highest DHFR inhibitory activity, with an IC50 value of 0.048 µM, which is approximately four times more potent than methotrexate. Compound CE11 exhibited similar docking performance to methotrexate, binding to the same site and engaging key residues such as Glh30, Phe31, Phe34, and Ser59. It also fit snugly in the hydrophobic pocket of modeled protein. Moreover, substantial hydrophobic interactions were noted between the ligand and the hydrophobic amino acid residues of DHFR. This effectively secured the derivative within the restricted substrate cavity. Furthermore, compound CE11 demonstrated a significant anticancer activity against MCF-7 breast cancer cell line, with an IC50 value of 5.37 ± 0.16 µM. Compounds CE3 and CE15 displayed better antibacterial activity compared to trimethoprim and comparable to ampicillin against the gram-positive bacteria S. aureus. Moreover, compounds CE3 and CE15 have shown better antibacterial activity than standard trimethoprim, ampicillin and tetracycline against the gram-negative bacteria, particularly P. aeruginosa and E. coli. Molecular docking analysis of CE3 revealed that it firmly entrapped into the active site of enzyme through hydrophobic interaction with hydrophobic residues. Additionally, it forms hydrogen bonds with important amino acid residues Ala7, Asn18, and Thr121 with excellent docking score and binding energy (-9.9, -71.77 kcal/mol). These interactions might be contributed to the significant DHFR inhibition and antimicrobial activity. The generated model holds potential value in facilitating the development of a novel category of DHFR inhibitors as anticancer and antimicrobial agents.

Targeting breast tumor extracellular matrix and stroma utilizing nanoparticles.

Breast cancer is a complicated malignancy and is known as the most common cancer in women. Considerable experiments have been devoted to explore the basic impacts of the tumor stroma, particularly the extracellular matrix (ECM) and stromal components, on tumor growth and resistance to treatment. ECM is made up of an intricate system of proteins, glycosaminoglycans, and proteoglycans, and maintains structural support and controls key signaling pathways involved in breast tumors. ECM can block different drugs such as chemotherapy and immunotherapy drugs from entering the tumor stroma. Furthermore, the stromal elements, such as cancer-associated fibroblasts (CAFs), immune cells, and blood vessels, have crucial impacts on tumor development and therapeutic resistance. Recently, promising outcomes have been achieved in using nanotechnology for delivering drugs to tumor stroma and crossing ECM in breast malignancies. Nanoparticles have various benefits for targeting the breast tumor stroma, such as improved permeability and retention, extended circulation time, and the ability to actively target the area. This review covers the latest developments in nanoparticle therapies that focus on breast tumor ECM and stroma. We will explore different approaches using nanoparticles to target the delivery of anticancer drugs like chemotherapy, small molecule drugs, various antitumor products, and other specific synthetic therapeutic agents to the breast tumor stroma. Furthermore, we will investigate the utilization of nanoparticles in altering the stromal elements, such as reprogramming CAFs and immune cells, and also remodeling ECM.

Localized Microrobotic Delivery of Enzyme-Responsive Hydrogel-Immobilized Therapeutics to Suppress Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), characterized by its aggressive metastatic propensity and lack of effective targeted therapeutic options, poses a major challenge in oncological management. A proof-of-concept neoadjuvant strategy aimed at inhibiting TNBC tumor growth and mitigating metastasis through a localized delivery of chemotherapeutics is reported in this paper. This approach addresses the limitations in payload capacity and stimuli responsiveness commonly associated with microrobotics in oncology. A hydrogel-based system is developed for the immobilization of chemotherapeutic agents, subsequently encapsulated within magnetically responsive microrobots. This design leverages external magnetic fields to facilitate the precise navigation and localization of the therapeutic agents directly to the tumor site. The efficacy of this approach is demonstrated in an animal model, in which a significant 14-fold reduction in tumor size and suppression of metastasis to critical organs such as the liver and lungs are observed. Crucially, the drug release mechanism is engineered to be responsive to the tumor microenvironment and is regulated by the overexpression of the enzymatic activity of matrix metalloproteinases (MMP2 and MMP9) in TNBC tumors, triggering the degradation of the hydrogel matrix, leading to controlled release of the immobilized therapeutic drug. This ensures that the therapeutic action is localized, reducing systemic toxicity and enhancing treatment efficacy. These findings suggest that this neoadjuvant approach holds promise for broader applications in other cancer types.

Network Pharmacology and In Silico Elucidation of Phytochemicals Extracted from Ajwa Dates (Phoenix dactylifera L.) to Inhibit Akt and PI3K Causing Triple Negative Breast Cancer (TNBC).

About 10-15% of all breast cancers comprise triple-negative breast cancer (TNBC), defined as cancer cells that lack receptors for the ER, PR, and HER2 protein receptors. Due to the absence of these receptors, treating TNBC using conventional chemotherapy is challenging and, therefore, requires the discovery of novel chemotherapeutic agents derived from natural sources. The current work was intended to study the potential phytochemicals of Ajwa dates (Phoenix dactylifera L.) with the predicted potential targets (namely, Akt and PI3K) to determine possible TNBC inhibitors. We harnessed network pharmacology, molecular docking, drug-likeness studies, Molecular Dynamics (MD) simulation, and binding free energy (MM-GBSA) calculation to get phytochemicals with potential effects against TNBC. Firstly, molecular docking was performed on 125 phytochemicals against the Akt and PI3K proteins utilizing PyRx. Then, the phytochemicals with the highest binding affinity (≤ -8.1 kcal/mol) were examined for in silico drug-likeness and toxicity profiles. Finally, phytochemicals with optimal druglikeness and toxicity profiles were studied by Molecular Dynamics (MD) simulation and binding free energy (MM-GBSA) to identify compounds that can form stable complexes. The results of the network pharmacology revealed that the Akt and PI3K proteins are potential targets of TNBC for the phytochemicals of Phoenix dactylifera L. used in this study. The outcomes of molecular docking displayed that among 125 phytochemicals, 42 of them (with a binding affinity ≤ -8.1 kcal/mol) have potentially inhibiting effects on both proteins PI3K and Akt expressed in TNBC. Then, the results of in silico drug-likeness identified seven phytochemicals with optimal pharmacokinetic profiles. Furthermore, toxicity studies showed that three phytochemicals (namely, Chrysoeriol, Daidzein, and Glycitein) did not cause any toxicities. Finally, the Molecular Dynamics (MD) simulation studies and binding free energy (MM-GBSA) verified that Daidzein stayed within the binding cavities of both proteins (Akt and PI3K) by establishing a stable protein-ligand complex during simulation. Taken together, the current work emphasizes the potential effects of Daidzein from Phoenix dactylifera L. against TNBC, and it can be further studied to establish it as a standard chemotherapy for TNBC.

Enhanced Anticancer Efficacy of Alkaline Plasma-Activated Water through Augmented RONS Production.

Despite notable advances in anticancer drug development, their manufacture and use pose environmental and health risks due to toxic byproducts, drug residue contamination, and cytotoxicity to normal cells. Therefore, developing cost-effective anticancer treatments with fewer toxic side effects and higher selectivity is essential to the advancement of highly effective anticancer therapies. Plasma-activated water (PAW) offers a green alternative to conventional chemical treatments as it reverts to water within days. However, the limited duration and dose of reactive oxygen and nitrogen species (RONS) in acidified PAW restrict its clinical deployment and the full understanding of their mechanism. In this study, we propose alkaline PAW as an innovative enhancement of the RONS technology. The alkaline PAW generated markedly superior RONS, with about 10 times higher levels of NO2-, H2O2, and ONOO-/O2•- than acidic PAW. The possible RONS generation pathways in alkaline PAW are analyzed by scavengers. In conventional acidic PAW, 70% of the H2O2 concentration is contributed by •OH but only about 20% in alkaline PAW. ONOO- is mainly formed through the reaction of O2•- with NO in alkaline pH, while in acidic PAW, it mainly forms from NO2- and H2O2. The results unveiled the synergistic and formidable anticancer effects of alkaline PAW against cancer cells, typified by an increase in intracellular ROS/RNS levels. Furthermore, alkaline PAW injection also effectively prevented xenograft tumor growth in mice. We systematically investigated this high-dose anticancer solution without using noble gases, toxic reagents, or extra energy consumption and successfully demonstrated the possibility of alkaline PAW being an effective and environmentally friendly therapeutic technology. The activity is closely linked to the RONS dose, and the generation pathway provides much-needed insight into the fundamental aspects of PAW chemistry required for the optimization of the biochemical activity of PAW.

Machine learning-based prognostic model of lactylation-related genes for predicting prognosis and immune infiltration in patients with lung adenocarcinoma

BackgroundHistone lactylation is a novel epigenetic modification that is involved in a variety of critical biological regulations. However, the role of lactylation-related genes in lung adenocarcinoma has yet to be investigated.MethodsRNA-seq data and clinical information of LUAD were downloaded from TCGA and GEO datasets. Unsupervised consistent cluster analysis was performed to identify differentially expressed genes (DEGs) between the two clusters, and risk prediction models were constructed by Cox regression analysis and LASSO analysis. Kaplan–Meier (KM) survival analysis, ROC curves and nomograms were used to validate the accuracy of the models. We also explored the differences in risk scores in terms of immune cell infiltration, immune cell function, TMB, TIDE, and anticancer drug sensitivity. In addition, single-cell clustering and trajectory analysis were performed to further understand the significance of lactylation-related genes. We further analyzed lactate content and glucose uptake in lung adenocarcinoma cells and tissues. Changes in LUAD cell function after knockdown of lactate dehydrogenase (LDHA) by CCK-8, colony formation and transwell assays. Finally, we analyzed the expression of KRT81 in LUAD tissues and cell lines using qRT-PCR, WB, and IHC. Changes in KRT81 function in LUAD cells were detected by CCK-8, colony formation, wound healing, transwell, and flow cytometry. A nude mouse xenograft model and a KrasLSL-G12D in situ lung adenocarcinoma mouse model were used to elucidate the role of KRT81 in LUAD.ResultsAfter identifying 26 lactylation-associated DEGs, we constructed 10 lactylation-associated lung adenocarcinoma prognostic models with prognostic value for LUAD patients. A high score indicates a poor prognosis. There were significant differences between the high-risk and low-risk groups in the phenotypes of immune cell infiltration rate, immune cell function, gene mutation frequency, and anticancer drug sensitivity. TMB and TIDE scores were higher in high-risk score patients than in low-risk score patients. MS4A1 was predominantly expressed in B-cell clusters and was identified to play a key role in B-cell differentiation. We further found that lactate content was abnormally elevated in lung adenocarcinoma cells and cancer tissues, and glucose uptake by lung adenocarcinoma cells was significantly increased. Down-regulation of LDHA inhibits tumor cell proliferation, migration and invasion. Finally, we verified that the model gene KRT81 is highly expressed in LUAD tissues and cell lines. Knockdown of KRT81 inhibited cell proliferation, migration, and invasion, leading to cell cycle arrest in the G0/G1 phase and increased apoptosis. KRT81 may play a tumorigenic role in LUAD through the EMT and PI3K/AKT pathways. In vivo, KRT81 knockdown inhibited tumor growth.ConclusionWe successfully constructed a new prognostic model for lactylation-related genes. Lactate content and glucose uptake are significantly higher in lung adenocarcinoma cells and cancer tissues. In addition, KRT81 was validated at cellular and animal levels as a possible new target for the treatment of LUAD, and this study provides a new perspective for the individualized treatment of LUAD.

Protective Effect of Silver Nanoparticles Against Cytosine Arabinoside Genotoxicity: An In Vivo Micronucleus Assay

Cancer treatments have harmful side effects, including genotoxic ones. Our previous research discovered that a specific silver nanoparticle (AgNPs) formulation could reduce the genotoxic effects of an alkylating agent, cyclophosphamide. This study aims to evaluate if this protective effect is observed against an antimetabolite anticancer agent, cytosine arabinoside (Ara-C). An erythrocyte micronucleus assay was conducted on BALB/c mice. A most significant effect was observed after the application scheme, including three doses of Ara-C and three subsequent doses of AgNPs, resulting in a 3.7 and 2.0-fold decrease in the frequency of micronucleated reticulocytes and accumulated erythrocytes, respectively. Current and previous studies reveal that AgNPs could be used as a genoprotector against the genotoxic damage produced by the currently used antineoplastic antimetabolites and alkylating agents. It was revealed that AgNPs could be considered a new class of promising synthetic antineoplastic genoprotectants along with the known class of derivatives from natural sources.

Oleanolic acid combined with aspirin plays antitumor roles in colorectal cancer via the Akt/NFκB/IκBα/COX2 pathway

Among the common malignancies, colorectal cancer (CRC) is often resistant to chemotherapy because of drug resistance and severe toxicity. Currently, aspirin is one of the most promising CRC chemopreventive drugs, both for primary prevention and for reducing the chance of recurrence and metastasis following radical surgery in patients with early-stage CRC. Oleanolic acid is a potential antineoplastic drug that has an antagonistic effect on many kinds of tumors. Network pharmacology, molecular docking, and in vitro experiments were performed to investigate whether OA combined with aspirin can enhance the anticancer effects of aspirin. As indicated by the network pharmacology results, oleanolic acid and aspirin can regulate multiple signaling pathways through multiple target proteins, including NFκB1\\IκBα\\PTGS2\\MAPK3\\PIK3CA. A series of cellular experiments demonstrated for the first time that oleanolic acid synergistically enhances aspirin to inhibit the proliferation and invasion of HCT116 and HT29 cells and induce S-phase arrest by regulating Akt/NFκB/IκBα/COX2 signaling pathway, thus synergistically enhancing the ability of aspirin to promote apoptosis of colorectal cancer cells. This study provides a novel approach to the use of fresh medications for the treatment of colorectal cancer and offers a theoretical foundation for the potential creation of aspirin derivatives based on oleanolic acid.

Prognostic, oncogenic roles, and pharmacogenomic features of AMD1 in hepatocellular carcinoma

Background AMD1 is the gene encoding S-adenosylmethionine decarboxylase 1. How AMD1 affects the prognosis of hepatocellular carcinoma (HCC) patients is unclear.MethodsUsing the Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma datasets, gene enrichment and immunological traits were compared between groups with high and low AMD1 expression. After altering AMD1 expression in HCC cells, cell viability, the clonal formation rate, and migration and invasion ability were detected. Univariate Cox regression analysis and Pearson correlation were used to screen for AMD1-related genes (ARGs). Multidimensional bioinformatic algorithms were utilized to establish a risk score model for ARGs.Results AMD1 expression was notably increased in the majority of cancer types. High AMD1 expression was associated with adverse outcomes and poorer immunotherapy response in HCC patients. AMD1 exhibited higher expression levels in HCC cell lines. The efficient inhibition of HCC cell proliferation, migration, and invasion in vitro can be achieved through the downregulation of AMD1. The AMD1-related risk score was constructed with the expression of 9 ARGs, and demonstrated high predictive efficacy in multiple validation cohorts. Patients with high risk scores exhibited greater resistance to classical chemotherapy drugs. The nomogram, which consists of age, stage, and the AMD1-related risk score, was used to calculate the probability of survival for each individual.ConclusionThe present study indicates that AMD1 functions as a potential role in HCC progression and may serve as a therapeutic target in HCC. This study constructed a novel AMD1-related scoring system for predicting the prognosis and treatment responsiveness of patients with HCC, enabling the prediction of prognosis and identification of potential treatment targets.

PI3K/mTOR Inhibitor VS-5584 Alters Expression of WNT Signaling Genes and Induces Apoptosis in Lung Adenocarcinoma Cells: In Vitro and In Silico Insight.

Lung cancer (LC) accounts for approximately 25% of all cancer cases, with 80-85% of these being non-small cell lung cancer (NSCLC). VS-5584 is a novel anti-cancer agent that specifically inhibits mTORC1/2 and class I PI3K isoforms. There is cross-talk between the PI3K-Akt-mTOR and WNT signaling pathways that are abnormally activated in NSCLC. In this study, we aimed to evaluate the anti-cancer effects of VS-5584 on A549 lung adenocarcinoma cells and changes in WNT signaling gene expression in vitro, while also correlating differentially expressed genes in silico. The effect of VS-5584 on A549 cell viability was assessed by the MTT assay. Apoptosis and cell cycle profiles were analyzed by flow cytometry, while WNT signaling gene expression was measured by quantitative RT-PCR. Differentially expressed genes (DEGs) in the TCGA LUAD and LUSC datasets were identified using the GEPIA2 platform. VS-5584 treatment induced apoptosis and caused cell cycle arrest at the G0/G1 phase in A549 cells. The mRNA expression levels of WNT signaling genes significantly decreased in treated cells. The expression of some upregulated DEGs in the datasets decreased in A549 cells treated with VS-5584. VS-5584 shows promise as an anti-cancer agent in the treatment of NSCLC by downregulating the expression of WNT signaling genes.

Cascade-Activatable Nanoprodrug System Augments Sonochemotherapy of Bladder Cancer.

Sonochemotherapy (SCT) has emerged as a powerful modality for cancer treatment by triggering excessive production of reactive oxygen species (ROS) and controlled release of chemotherapeutic agents under ultrasound. However, achieving spatiotemporally controlled release of chemotherapeutic agents during ROS generation is still an enormous challenge. In this work, we developed a cascade-activated nanoprodrug (CAN) system that utilizes a reversible covalent Schiff base mixed with a hypoxia-activatable camptothecin (CPT) prodrug. Briefly, the designed fluorinated CAN system is self-assembled into nanoparticles under aqueous conditions, which could penetrate deep tumors to offer sufficient oxygen for ultrasound-triggered ROS production. Consequently, the nanoparticles substantially exacerbated the hypoxia of the tumor microenvironment (TME) by elevating oxygen consumption. The aggravated hypoxia in turn served as a positive amplifier to boost the tumor-specific CPT release of Azo-CPT prodrug, which made up for the insufficient treatment efficacy of sonodynamic therapy (SDT). On this basis, we observed a substantial reduction, approximately 3.5-fold, in the half-maximal inhibitory concentration (IC50) of the CAN system compared to that of free CPT in bladder cancer cell lines (T24). Furthermore, the CAN system demonstrated potent antitumor efficacy with reduced side effects, resulting in regression and eradication of T24 tumors in various mouse models. In summary, the CAN system can be easily extended by incorporating different chemotherapeutic agents, showing great potential to revolutionize the clinical management paradigm of bladder cancer.

Paclitaxel-induced Hypersensitivity Reaction

Abstract An immunological response that results in an adverse reaction due to a certain drug is known as a hypersensitivity reaction (HSR). Such type of reactions is seen with antineoplastic agents. HSR is commonly seen with one of the chemotherapeutic agents, namely, paclitaxel. Occurrence of such reactions can be suppressed with the administration of premedications (dexamethasone 20 mg intravenous [IV], diphenhydramine 50 mg IV, and famotidine 20 mg IV). Mainly, the paclitaxel consists of paclitaxel IP, polyoxyl 35, castor oil IP (Cremophor ELP), and dehydrated alcohol IP. The mechanism of this reaction is not known exactly, but it is believed that the reaction may be occurring due to paclitaxel itself or its vehicle castor oil IP (Cremophor ELP). Molecules present in Cremophor ELP are found to be similar in structure to certain nonionic block copolymers that activate complement proteins (the proteins involved in various immune processes).