Inhibit Cancer Cell Growth Research Articles

Integrating computational methods and in vitro experimental validation reveals the pharmacological mechanism of Selaginella bryopteris (L.) Baker targeting major proteins in breast cancer

Breast cancer remains a significant global health challenge, necessitating the exploration of novel therapeutic options. The present study employs an integrated approach encompassing network pharmacology, molecular docking, molecular dynamics simulations, and in-vitro validation to investigate the potential of Selaginella bryopteris in breast cancer treatment. Initial network pharmacology analysis revealed different potential targets and pathways associated with breast cancer that could be modulated by S. bryopteris phytochemical constituents. Molecular docking and dynamics simulations further elucidated the stability and dynamics of protein-ligand complexes (lanaroflavone–EGFR and sequoiaflavone-CTNNB1). The in-vitro assays demonstrated the ability of S. bryopteris crude extract to inhibit cancer cell growth (IC50 - 78.34 μg/mL) migration and invasion, supporting the computational predictions. The integrated approach employed in the present study offers a robust framework for the systematic exploration of S. bryopteris in drug discovery as a promising candidate for breast cancer treatment.

The impact of Trifolium pratense extract on apoptosis and autophagy in NALM-6 cells: implications for B-ALL intervention.

B-cell acute lymphoblastic leukemia (B-ALL), a prevalent malignancy predominantly affecting children, poses challenges such as drug resistance and cytotoxicity despite available treatment methods. The persistence of these challenges underscores the necessity for innovative therapeutic approaches to enhance efficacy. Natural compounds derived from plants, recognized for their potential to inhibit cancer cell growth, have drawn attention. Trifolium pratense extract, known for its significant anticancer properties in previous studies, was the focus of this investigation. This experimental study aimed to explore the impact of T. pratense extract on apoptosis and autophagy in NALM-6 cells. The cells were exposed to varying concentrations of the extract at specific time intervals, with viability and metabolic activity assessed using Trypan blue exclusion and MTT assays. Flow cytometry was employed to evaluate apoptosis using Annexin V/PI staining and ROS production using DCFH-DA staining. Real-time PCR was used to quantify gene expression related to apoptosis, autophagy, and oxidative stress, with data analysis performed using GraphPad PRISM software. Trifolium pratense extract demonstrated the capacity to induce apoptosis, autophagy, and significantly increase ROS production in NALM-6 cells. These effects were facilitated by the upregulation of corresponding genes. The MTT assay revealed an IC50 of 231 μg/mL at 48 h, and Flow cytometry analysis showed a 51.8% increase in apoptosis in this cell line. Overall, this study emphasizes the effectiveness of T. pratense extract in inducing autophagy and apoptosis pathways in NALM-6 cells derived from B-cell acute lymphoblastic leukemia, suggesting its potential as a candidate for further investigation as a supplement in ALL treatment.

Abutilon indicum-mediated green synthesis of NiO and ZnO nanoparticles: Spectral profiling and anticancer potential against human cervical cancer for public health progression

BackgroundIntegrating nanomedicines for targeted cancer treatment and pursuing medicinally valuable components from nature are crucial for sustainable, potent alternatives to synthetic drugs in combating fatal diseases like cancer. Hence, a green synthesis of nickel oxide (NiO NPs) and zinc oxide nanoparticles (ZnO NPs) has been carried out by using the leaf extract of medicinally important plant Abutilonindicum. This sustainable approach to medical developments not only reduces the environmental effect of standard synthesis methods and offers new options for novel cancer therapeutics, but it also advances public health by using natural resources in a sustainable manner. MethodsThe synthesized nanoparticles were characterized by employing spectro-analytical techniques like UV–vis, FT-IR, SEM and powder XRD. Synthesized nanparticles were evaluated in the human cervical cancer cells (HeLa). ResultsNi-O stretching vibrations were observed at 402 cm−1, whereas that of Zn-O stretching was observed at 409 cm−1in the FT-IR spectrum, confirming the formation of nanoparticles. The XRD pattern revealed the crystallite size range of 1.35–2.84 nm for NiO NPs and 7.71–56.80 nm for ZnO NPs. The morphology of the nanoparticles, as indicated by the SEM images, was rod-like for NiO NPs and rock-shaped for ZnO NPs. Further, the cancer cell growth inhibition activity of the nanoparticles was examined by MTT assay against human cervical cancer cells (HeLa) proliferation and compared with cisplatin. MTT assay elucidated the significant anticancer efficacy of the synthesized nanoparticles, showcasing low IC50 values of 29±0.5 µg/ml for NiO NPs and 32±0.7 µg/ml for ZnO NPs. Furthermore, the anticancer activity of the NiO NPs was investigated using the Trypan blue dye exclusion technique, emphasizing the pronounced cytotoxic impact of NiO NPs on cancer cell viability. The outcomes underscore the notable anticancer properties of plant extract mediated metal nanoparticles as promising contenders for advancing cancer treatment modalities.

Effect of Beta Vulgaris Extract on the Michigan Cancer Foundation-7 (MCF-7) and Rat Embryo Fibroblast (REF)

The study aimed to study the cytotoxic effect of the aqueous extract of Beta vulgaris on the breast carcinoma cell MCF-7 and the normal cell REF. Six diluted concentrations of the aqueous extract of the plant roots including (7.8, 31.25, 62.5, 125, 250, 500) µg/ml, with three exposure periods of 24, 48, and 72 hrs. The quantitative estimation of the active compounds of the aqueous extract was calculated. It was found that the aqueous extract of plant contains many active compounds such as (tannins, phenols, flavonoids and glycosides). The effect of the extract on normal REF cells after an exposure period of 72 hrs, which is represented by the concentration that causes inhibition of the proliferation of normal REF cells by 50%, is (IC50) with the aqueous extract of B. vulgaris was (6.35) mg/ml. The aqueous extract of plant was tested to detect the cytotoxic effect of the aqueous extract and all concentrations used on the MCF-7 breast cancer cell. The results showed that increase in the percentage rate of inhibition of cancer cell growth was observed during the three exposure periods of 24, 48, and 72 hrs. There is significant differences at (p≤0.05) and compared with the control. The rate of inhibition ranges at the lowest concentration 500 µg/ml were (92.204±1.455) (93.616 ±1.376) and (95.325±1.407) respectively.

Repurposing Valrubicin as a Potent Inhibitor of Ovarian Cancer Cell Growth.

Ovarian cancer (OC) is a leading cause of cancer-related mortality among women, and there remains a significant unmet need for new therapeutic agents to improve patient outcomes. This study aimed to explore drug repositioning by screening a library of Food and Drug Administration (FDA)-approved compounds to identify those with therapeutic potential against OC. We also aimed to elucidate the molecular mechanisms of action of such compounds to better understand how they inhibit cancer cell proliferation. Using the WST-1 assay, a library of 1710 FDA-approved drugs was screened to evaluate their effects on OC cell proliferation. The molecular mechanisms underlying the effects of selected compounds were assessed through terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunoblot analysis. Screening of FDA-approved libraries revealed valrubicin as a potent inhibitor of OVCAR8 cell proliferation and SKOV3 and A2780 cell growth. Furthermore, valrubicin treatment led to increased DNA fragmentation, as evidenced by the TUNEL assay, and activated apoptosis signaling through enhancement of cleaved caspase-3 and poly(ADP-ribose) polymerase levels. Valrubicin, through drug repositioning, can be applied as a new therapeutic agent for OC.

Identification of sanguinarine as c-MYC transcription inhibitor through enhancing the G-quadruplex-NM23-H2 interactions

c-MYC is a proto-oncogene ubiquitously overexpressed in various cancers. The formation of G-quadruplex (G4) structures within the c-MYC promoter region can regulate its transcription by interfering with protein binding. Consequently, small molecules targeting c-MYC G4 have emerged as promising anticancer agents. Herein, we report that sanguinarine (SG) and its analogs exhibit a high affinity for c-MYC G4 and potently modulate G4-protein interactions within a natural product library. Notably, SG uniquely enhances NM23-H2 binding to c-MYC G4, both in vitro and in cellular contexts, leading to c-MYC transcriptional repression and subsequent inhibition of cancer cell growth in an NM23-H2-dependent manner. Mechanistic studies and molecular modeling suggest that SG binds to the c-MYC G4/NM23-H2 interface, acting as an orthosteric stabilizer of the DNA-protein complex and preventing c-MYC transcription. Our findings identify SG as a potent c-MYC transcription inhibitor and provide a novel strategy for developing G4-targeting anticancer therapeutics through modulation of G4-protein interactions.

Engineered CD4 T cells for in vivo delivery of therapeutic proteins

The CD4 T cell, when engineered with a chimeric antigen receptor (CAR) containing specific intracellular domains, has been transformed into a zero-order drug-delivery platform. This introduces the capability of prolonged, disease-specific engineered protein biologics production, at the disease site. Experimental findings demonstrate that CD4 T cells offer a solution when modified with a CAR that includes 4-1BB but excludes CD28 intracellular domain. In this configuration, they achieve ~3X transduction efficiency of CD8 T cells, ~2X expansion rates, generating ~5X more biologic, and exhibit minimal cytolytic activity. Cumulatively, this addresses two main hurdles in the translation of cell-based drug delivery: scaling the production of engineered T cell ex vivo and generating sufficient biologics in vivo. When programmed to induce IFNβ upon engaging the target antigen, the CD4 T cells outperforms CD8 T cells, effectively suppressing cancer cell growth in vitro and in vivo. In summary, this platform enables precise targeting of disease sites with engineered protein-based therapeutics while minimizing healthy tissue exposure. Leveraging CD4 T cells' persistence could enhance disease management by reducing drug administration frequency, addressing critical challenges in cell-based therapy.

Optimizing Titanium Carbide-Silver Oxide Nanostructures for Targeted Cancer Therapy: Synthesis, Functionalization, and In Vitro Evaluations.

Introduction Cancer remains a significant health challenge, and nanoparticles (NPs) are promising candidates for cancer treatment due to their unique physicochemical properties and ability to selectively target tumour cells. Two-dimensional (2D) nanomaterials, such as MXenes, have attracted interest due to their electronic structures, optical properties, catalytic abilities, and exceptional physicochemical attributes. MXenes are highly suitable for surface functionalization or modification, and their unique properties make them promising candidates for various applications in the biological field. Silver-based compounds have shown remarkable potential in biomedical fields, with silver oxide (Ag₂O) NPs finding applications in various domains. The fabrication of titanium carbide (Ti₃C₂)-Ag₂O heterostructures has been investigated for their anti-cancer properties by conducting cell viability assays on different cell lines. Aim To synthesize and characterize Ti₃C₂-Ag₂O, and to assess its in vitro anti-cancer activity. Materials and methods Ti₃C₂ synthesis begins by dissolving Ti₃AlC₂ powder in a 50% v/v hydrofluoric (HF) acid solution, allowing the aluminium to be etched away. This process should be conducted with continuous stirring for 24 to 48 hours at ambient temperature. Following this, filter the resulting suspension to eliminate aluminium particles and HF, and subsequently wash the Ti₃C₂ MXene with distilled water until a neutral pH is attained. The MXene should then be dispersed in ethanol, and sonication in deionized (DI) water or an alternative solvent should be employed to achieve exfoliation into monolayer or few-layer MXenes. To prepare Ag₂O NPs, dissolve silver nitrate (AgNO₃) in DI water to create a 0.1 M solution, and concurrently prepare a separate 0.1 M sodium hydroxide (NaOH) solution. Introduce the NaOH solution to the AgNO₃ while stirring until a precipitate is observed. The mixture should then be filtered, washed with distilled water, and the NPs dried at 60°C for 12 hours. To fabricate the MXene-Ag₂O composite, disperse the MXene nanoflakes in a solvent through sonication, incorporate the Ag₂O NPs, and stir the mixture for 24 hours. Finally, centrifuge the resultant mixture to isolate the composite, wash it with solvent, and dry it under vacuum conditions. Results The presence of Ag₂O particles on Ti₃C₂ nanosheets was observed, and the high crystallinity of the compound was confirmed through X-ray diffraction (XRD), energy-dispersive spectroscopy (EDS), and scanning electron microscopy (SEM) analyses. These tests verified that the compound was free of impurities and exhibited anti-cancer properties. Conclusion The synthesis of Ti₃C₂ MXenes and Ag₂O NPs was achieved and confirmed through structural characterization methods, including SEM, XRD, and EDS. SEM provided detailed insights into the morphology and distribution of the nanostructures, while XRD and EDS verified their phase purity and elemental composition. Functionalization strategies were employed to enhance the stability and bioactivity of the nanocomposites. In vitro evaluations demonstrated promising anti-cancer activity, indicating that the Ti₃C₂-Ag₂O composites effectively target and inhibit cancer cell growth.

Synergistic Inhibition of Pancreatic Cancer Cell Growth and Migration by Gemcitabine and Withaferin A.

Pancreatic cancer remains one of the most lethal malignancies due to its aggressive nature and resistance to conventional therapies. This study investigates the anti-proliferative, pro-apoptotic, and anti-migratory effects of Gemcitabine (GC) and Withaferin A (WFA) on pancreatic cancer cell lines PANC-1 and Hs766t. The MTS assay revealed that both compounds effectively inhibit cell proliferation, with WFA showing a stronger effect in Hs766t cells. Flow cytometry analysis demonstrated that GC and WFA, particularly in combination, significantly induce apoptosis in both cell lines. Migration assays confirmed the potent inhibition of cell migration by both compounds, with the combination treatment being the most effective. Furthermore, actin cytoskeleton analysis indicated substantial changes in cell morphology and stiffness, suggesting that GC and WFA disrupt the structural integrity of cancer cells. Additionally, the study highlights a ROS-mediated mechanism underlying the effects of GC and WFA, as evidenced by increased ROS levels following treatment, which were attenuated by N-acetylcysteine. Importantly, NF-κB activity was significantly modulated, with WFA reducing NF-κB activation induced by GC, potentially contributing to the synergistic pro-apoptotic effect of the combination. These findings suggest that the combination of GC and WFA may offer a synergistic therapeutic approach for treating pancreatic cancer by targeting multiple aspects of tumor cell behavior.

Protective Effects of Antimicrobial Peptide Microcin J25 (MccJ25) Isolated From Escherichia coli Against Breast Cancer Cells

ABSTRACTMicrocins are antimicrobial peptides (AMPs) with low molecular weight, which are produced by Enterobacterales and have broad‐spectrum antibacterial activity. Alternative approaches like AMPs could help conventional anticancer treatments to fight malignant cells. The present study endeavors to examine the antitumor activity of microcins isolated from different Enterobacterales strains. In total, 120 Enterobacterales isolates were examined after identification. Subsequently, the bacteria were subjected to an agar diffusion test to assess their antibacterial efficacy. Positive isolates were further examined for the presence of Mccj25 using PCR. The cytotoxic effects of isolates harboring the microcin gene were explored using quantitative real‐time PCR (RT‐qPCR) and the MTT test on breast cancer cells. In addition, the expression levels of BCL2 and STAT3 genes were evaluated, and apoptosis was quantified using flow cytometry. The repair rate of normal cells was determined using a scratch assay. The findings obtained from the phenotypic and biochemical assays have duly verified and established the categorization of the Enterobacterales. After conducting the agar diffusion test, a total of 25 isolates of Escherichia coli and Klebsiella pneumoniae displaying inhibition zones were chosen as suitable specimens possessing AMPs. The analysis conducted on the expression of the Mccj25 gene within the aforementioned isolates indicated that Isolate 83 exhibited significant expression of the Mccj25 gene. The extract obtained from this isolate on the breast cancer cell line exhibited the most significant degree of toxicity after 48 h. Furthermore, the treatment of breast cancer cells with Isolate 83 showed that the rate of apoptosis was about 86%, and the expression of BCL2 and STAT3 genes decreased. Contrarily, it potentiated the reparative ability of nontumoral fibroblasts, supporting the in vitro safety toward normal cells and, at the same time, the selectivity against malignant ones. In summary, our results highlighted a significant growth suppression of breast cancer cells with an escalated rate of cellular demise via the apoptosis pathway.

Migfilin promotes autophagic flux through direct interaction with SNAP29 and Vamp8.

Autophagy plays a crucial role in cancer cell survival by facilitating the elimination of detrimental cellular components and the recycling of nutrients. Understanding the molecular regulation of autophagy is critical for developing interventional approaches for cancer therapy. In this study, we report that migfilin, a focal adhesion protein, plays a novel role in promoting autophagy by increasing autophagosome-lysosome fusion. We found that migfilin is associated with SNAP29 and Vamp8, thereby facilitating Stx17-SNAP29-Vamp8 SNARE complex assembly. Depletion of migfilin disrupted the formation of the SNAP29-mediated SNARE complex, which consequently blocked the autophagosome-lysosome fusion, ultimately suppressing cancer cell growth. Restoration of the SNARE complex formation rescued migfilin-deficiency-induced autophagic flux defects. Finally, we found depletion of migfilin inhibited cancer cell proliferation. SNARE complex reassembly successfully reversed migfilin-deficiency-induced inhibition of cancer cell growth. Taken together, our study uncovers a new function of migfilin as an autophagy-regulatory protein and suggests that targeting the migfilin-SNARE assembly could provide a promising therapeutic approach to alleviate cancer progression.

Senegenin suppresses hepatocellular carcinoma by regulating O-GlcNAcylation.

Based on current knowledge, hepatocellular carcinoma (HCC) is a condition with numerous etiologies and risk factors. However, the pathogenesis of HCC remains unclear. To investigate the roles of senegenin and O-GlcNAcylation in the growth and metastasis of HCC. The levels of O-linked N-acetylglucosamine transferase (OGT) and O-GlcNAcylation in HCC cells and tissues were detected using western blot analysis. The effects of senegenin and O-GlcNAcylation on the proliferation of HCC cells were investigated in vitro using cell counting kit-8 and clonogenic assays. The potential effects of senegenin and O-GlcNAcylation on HCC metastasis were examined using the transwell migration assay. O-GlcNAcylation levels were altered via drug treatment and lentiviral infection, and western blot analysis was used to detect proteins involved in various pathways. Western blot analysis revealed that OGT and O-GlcNAcylation levels were significantly elevated in HCC tissues and cells. O-GlcNAcylation levels in HCC cells were significantly altered by drug treatment and lentiviral infection. An increase in the glycosylation level was linked to enhanced proliferation, invasiveness, clonogenicity, and metastatic potential of cancer cells. O-GlcNAcylation induced by senegenin was found to slow the proliferation and migration of HCC cells. The levels of proteins involved in nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, which are associated with endoplasmic reticulum stress, were altered. Senegenin lowers O-GlcNAcylation levels, decreases OGT expression, and inhibits cancer cell growth and metastasis by regulating proteins involved in NF-κB and JNK pathways.

Abstract B031: Alternate pain management strategies: targeting pancreatic cancer-related pain with Flavonoid

Abstract Purpose For up to 90% of cancer patients, pain is a substantial symptom, contributing to morbidity and, possibly, mortality. In this study we sought to test the hypothesis that a flavonoid, derived from Cannabis, and previously shown to suppress cancer cell growth in vitro and tumor progression in mice in vivo, could also reduce the pain caused by pancreatic tumors in vivo. Methods A subcutaneous tumor in the dorsum of C57BL/6 mouse was generated by sub- dermal injection of KPC mouse pancreatic cancer cell line (ATCC). All the mice were video recorded to observe and analyze their spontaneous pain-related behaviors, including facial washing, dorsal hunching, dorsal skin twitch, licking of dorsal skin and overall locomotion around the cage. Two five minute recording sessions were analyzed by a blinded observer during times before the cancer cell injection (Baseline), after tumor growth, to about 8mm diameter (30d and 37d post-injection) and just before and then 24h after intra-tumor injection of the flavonoid ( Group A: FBL-03G, 1 nmole in 100µL) or Vehicle(100µL; Group B). Pain-related behavioral changes were averaged from the two recording sessions and analyzed from Baseline, just before FBL-03G and 24h after and compared between test compound-and vehicle injected groups (n=7 in each), using non-parametric statistics. Results Facial washing (events/5min) was: reduced to 87% of Baseline in tumor-bearing mice, then increased by 150% at 24h post-injection in Group A (FBL-03G); reduced to 65% of Baseline in tumor-bearing mice of Group B, then reduced a further 9% by Vehicle. Dorsal hunching, which events occur only after tumor growth (Baseline =0), was reduced at 24h by 62% in Group A but increased by 75% in Group B. Dorsal twitch, also absent before tumor growth, was reduced by 64% in Group A, but increased by 19% in Group B. Dorsal skin licking was reduced from Baseline by 33% in tumor-bearing mice of Group A, then increased by 76% after FBL-03g injection whereas licking, reduced by 22% by tumors in Group B and then by an additional 4% by vehicle (Group B). Tumors reduced locomotion by 58% in Group A, which was reversed by 32% after FBL-03g (Group A); vehicle injection resulted in a 38% reduction in locomotion (Group B). Thus, in 4 of the 5 pain-related behaviors from tumors quantitated symptoms were reversed by FBL-03G and oppositely affected, or not at all, by Vehicle. Conclusions These results indicate a substantial relief of spontaneous pain-related pain in this mouse model of pancreatic cancer. Such an acute effect occurs much more rapidly than the previously published in vitro suppression of KPC cell growth (assayed after 9-12d of treatment) or the reduction of tumor size (1-7 weeks) in vivo and suggest that the anti-hyperalgesic affect is due to mechanisms that do not involve reduction in tumor mass. The findings, using a single dose and a small number of mice, appear promising for further studies that examine a range of doses or FBL-03G and its actions in intra-pancreatic tumors. Citation Format: Sayeda Yasmin-Karim, Suheera Haq, Mike Makrigiorgos, Gary Strichartz, Geraud Richards, Natasha Rayman. Alternate pain management strategies: targeting pancreatic cancer-related pain with Flavonoid [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B031.

ER membrane remodeling by targeting RTN4 induces pyroptosis to facilitate antitumor immune.

Pyroptosis is an identified programmed cell death that has been highly linked to endoplasmic reticulum (ER) dynamics. However, the crucial proteins for modulating dynamic ER membrane curvature change that trigger pyroptosis are currently not well understood. In this study, a biotin-labeled chemical probe of potent pyroptosis inducer α-mangostin (α-MG) was synthesized. Through protein microarray analysis, reticulon-4 (RTN4/Nogo), a crucial regulator of ER membrane curvature, was identified as a target of α-MG. We observed that chemically induced proteasome degradation of RTN4 by α-MG through recruiting E3 ligase UBR5 significantly enhances the pyroptosis phenotype in cancer cells. Interestingly, the downregulation of RTN4 expression significantly facilitated a dynamic remodeling of ER membrane curvature through a transition from tubules to sheets, consequently leading to rapid fusion of the ER with the cell plasma membrane. In particular, the ER-to-plasma membrane fusion process is supported by the observed translocation of several crucial ER markers to the "bubble" structures of pyroptotic cells. Furthermore, α-MG-induced RTN4 knockdown leads to PKM2-dependent conventional caspase-3/GSDME cleavages for pyroptosis progression. In vivo, we observed that chemical or genetic RTN4 knockdown significantly inhibited cancer cells growth, which further exhibited an antitumor immune response with anti-PD-1. In translational research, RTN4 high expression was closely correlated with the tumor metastasis and death of patients. Taken together, RTN4 plays a fundamental role in inducing pyroptosis through the modulation of ER membrane curvature remodeling, thus representing a prospective druggable target for anticancer immunotherapy.

Boehmeria Nivea Extract (BNE-RRC) Reverses Epithelial-Mesenchymal Transition and Inhibits Anchorage-Independent Growth in Tumor Cells.

The epithelial-mesenchymal transition (EMT) phenotype, identified as a significant clinical indicator in regard to cancer, manifests as a biological process wherein cells transition from having epithelial to mesenchymal characteristics. Physiologically, EMT plays a crucial role in tissue remodeling, promoting healing, repair, and responses to various types of tissue damage. This study investigated the impact of BNE-RRC on oral cancer cells (KB) and revealed its significant effects on cancer cell growth, migration, invasion, and the EMT. BNE-RRC induces the epithelial-like morphology in KB cells, effectively reversing the EMT to a mesenchymal-epithelial transition (MET). Extraordinarily, sustained culturing of cancer cells with BNE-RRC for 14 days maintains an epithelial status even after treatment withdrawal, suggesting that BNE-RRC is a potential therapeutic agent for cancer. These findings highlight the promise of BNE-RRC as a comprehensive therapeutic agent for cancer treatment that acts by inhibiting cancer cell growth, migration, and invasion while also orchestrating a reversal of the EMT process. In this study, we propose that BNE-RRC could be an effective agent for cancer treatment.

NF-κB-activated oncogene inhibition strategy for cancer gene therapy.

NF-κB is a promising target for cancer treatment because of its overactivation in almost all cancers but countless NF-κB inhibitors rarely became clinical drugs due to side effects. In contrast to traditional cancer treatments aimed at inhibiting NF-κB activity, this study develop a novel approach termed HOPE, which focuses on activating the exogenous effector gene CRISPR-Cas13a within cancer cells, achieved by utilizing the NF-κB-specific promoter DMP previously constructed, then targets and suppresses the expression of oncogenes TERT, PLK1, KRAS and MYC at mRNA level. We evaluated the antitumour effects of HOPE in various cultured cells and confirmed it could induce obvious the death of cancer cells without affecting normal cells. By packaging HOPE into adeno-associated virus (AAV) and intravenously injected it to treat mice that were subcutaneously transplanted with colorectal cancer. This validated that rAAV-HOPE could significantly inhibit tumour growth without side effects. Based on the scRNA-seq data, we observed that HOPE could activate the immune system and decrease the proportion of cancer cells, particularly reducing the stemness of cancer cells. This study elucidates an important role of HOPE in inhibiting cancer cell growth both in vitro and in vivo, additionally provides a novel therapeutic technology for cancer gene therapy.

Programming DNA Nanoassemblies into Polyvalent Lysosomal Degraders for Potent Degradation of Pathogenic Membrane Proteins.

Lysosome-targeting chimera (LYTAC) shows great promise for protein-based therapeutics by targeted degradation of disease-associated membrane or extracellular proteins, yet its efficiency is constrained by the limited binding affinity between LYTAC reagents and designated proteins. Here, we established a programmable and multivalent LYTAC system by tandem assembly of DNA into a high-affinity protein degrader, a heterodimer aptamer nanostructure targeting both pathogenic membrane protein and lysosome-targeting receptor (insulin-like growth factor 2 receptor, IGF2R) with adjustable spatial distribution or organization pattern. The DNA-based multivalent LYTACs showed enhanced efficacy in removing immune-checkpoint protein programmable death-ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) in tumor cell membrane that respectively motivated a significant increase in T cell activity and a potent effect on cancer cell growth inhibition. With high programmability and versatility, this multivalent LYTAC system holds considerable promise for realizing protein therapeutics with enhanced activity.

The vitamin D analog EB1089 sensitizes triple-negative breast cancer cells to the antiproliferative effects of antiestrogens

PurposePatients bearing estrogen receptor (ER)α-negative breast cancer tumors confront poor prognosis and are typically unresponsive to hormone therapy. Previous studies have shown that calcitriol, the active vitamin D metabolite, can induce ERα expression in ERα-negative cells. EB1089, a calcitriol analog with reduced calcemic effects, exhibits greater potency than calcitriol in inhibiting cancer cell growth. However, the impact of EB1089 on ERα expression in triple-negative breast cancer (TNBC) cells remains unexplored. This study aims to investigate whether EB1089 could induce functional ERα expression in TNBC cell lines, potentially enabling the antiproliferative effects of antiestrogens. Materials and methodsTNBC cell lines HCC1806 and HCC1937 were treated with EB1089, and ERα expression was analyzed using real-time PCR and Western blots. The transcriptional activity of induced ERα was evaluated through a luciferase reporter assay. The antiproliferative effects of tamoxifen and fulvestrant antiestrogens were assessed using the sulforhodamine B assay in the EB1089-treated cells. ResultsOur findings indicated that EB1089 significantly induced ERα mRNA and protein expression in TNBC cells. Moreover, EB1089-induced ERα exhibited transcriptional activity and effectively restored the inhibitory effects of antiestrogens, thereby suppressing cell proliferation in TNBC cells. ConclusionEB1089 induced the expression of functional ERα in TNBC cells, restoring the antiproliferative effects of antiestrogens. These results highlight the potential of using EB1089 as a promising strategy for re-establishment of the antiproliferative effect of antiestrogens as a possible management for TNBC. This research lays the foundation for potential advancements in TNBC treatment, offering new avenues for targeted and effective interventions.

MEN1 Deficiency-Driven Activation of the β-Catenin-MGMT Axis Promotes Pancreatic Neuroendocrine Tumor Growth and Confers Temozolomide Resistance.

O6-methylguanine DNA methyltransferase (MGMT) removes alkyl adducts from the guanine O6 position (O6-MG) and repairs DNA damage. High MGMT expression results in poor response to temozolomide (TMZ). However, the biological importance of MGMT and the mechanism underlying its high expression in pancreatic neuroendocrine tumors (PanNETs) remain elusive. Here, it is found that MGMT expression is highly elevated in PanNET tissues compared with paired normal tissues and negatively associated with progression-free survival (PFS) time in patients with PanNETs. Knocking out MGMT inhibits cancer cell growth in vitro and in vivo. Ectopic MEN1 expression suppresses MGMT transcription in a manner that depends on β-Catenin nuclear export and degradation. The Leucine 267 residue of MEN1 is crucial for regulating β-Catenin-MGMT axis activation and chemosensitivity to TMZ. Interference with β-Catenin re-sensitizes tumor cells to TMZ and significantly reduces the cytotoxic effects of high-dose TMZ treatment, and MGMT overexpression counteracts the effects of β-Catenin deficiency. This study reveals the biological importance of MGMT and a new mechanism by which MEN1 deficiency regulates its expression, thus providing a potential combinational strategy for treating patients with TMZ-resistant PanNETs.

Formulation and in-vitro anticancer activity of nilotinib immediate release and ibrutinib sustained release pellets

Background: Blood cancer is a significant contributor to mortality rates worldwide, and its prevalence is projected to rise on a global scale. This trend places considerable strain on healthcare systems and necessitates the expedited development of innovative treatments by pharmaceutical firms to remain competitive. Conventional pellets produce rapid plasma drug levels, but they might cause side effects, decrease effectiveness, and lead to poor therapeutic management. Ibrutinib and Nilotinib are employed to treat leukemia patients. Methodology: The current research aims to formulate, characterize, and anticancer effect of Nilotinib immediate release (NIR) and Ibrutinib sustained release (ISR) seal sugar-coated pellets. Micrometric properties estimated the characterization of the drug pellets, and surface morphology was estimated using scanning electron microscopy. Drug excipient compatibility studies, stability studies, and in-vitro drug release were accessed. Result & Discussion: The results of pellet formulations FNI-1 to FNI-5 showed that FNI-5 formulations showed 100±6.0 µm size and possessed excellent mechanical strength for giving pellets a good self-life; also, due to the higher drug content up to 99%, FNI-5 was the best suited for pellet formulation and because NIR showed 99.18 ± 2.12 drug release at 2h and ISR 99.03±3.74% up to 12h so that anticancer concentration maintained for prolonged period. The standard dose for cytotoxicity against the THP-1 cell line of Nilotinib was found to be 200 mg, and the maintenance oral dose of Ibrutinib was 140mg, with four times the intake of the drug up to 560 mg. In an in vitro study in FNI-5 (final formulation), the dose of Ibrutinib was reduced to 420 mg. Conclusion: A synergistic effect of Ibrutinib and nilotinib drugs was observed in the inhibition of cancer cell growth, with an IC50 value of 4.585 µg/mL