Antitumor Effects Research Articles

Pharmacological induction of MHC-I expression in tumor cells revitalizes T cell antitumor immunity.

Antigen presentation by major histocompatibility complex class I (MHC-I) is crucial for T cell-mediated killing, and aberrant surface MHC-I expression is tightly associated with immune evasion. To address MHC-I downregulation, we conducted a high-throughput flow cytometry screen, identifying bleomycin (BLM) as a potent inducer of cell surface MHC-I expression. BLM-induced MHC-I augmentation rendered tumor cells more susceptible to T cells in coculture assays and enhanced antitumor responses in an adoptive cellular transfer mouse model. Mechanistically, BLM remodeled the tumor immune microenvironment, inducing MHC-I expression in a manner dependent on ataxia-telangiectasia mutated/ataxia telangiectasia and Rad3-related-NF-κB. Furthermore, BLM improved T cell-dependent immunotherapeutic approaches, including bispecific antibody therapy, immune checkpoint therapy, and autologous tumor-infiltrating lymphocyte therapy. Importantly, low-dose BLM treatment in mouse models amplified the antitumor effect of immunotherapy without detectable pulmonary toxicity. In summary, our findings repurpose BLM as a potential inducer of MHC-I, enhancing its expression to improve the efficacy of T cell-based immunotherapy.

Preparation of Biomimetic Selenium-Baicalein Nanoparticles and Their Targeted Therapeutic Application in Nonsmall Cell Lung Cancer.

In this study, we prepared bionic selenium-baicalein nanoparticles (ACM-SSe-BE) for the targeted treatment of nonsmall cell lung cancer. Due to the coating of the A549 membrane, the system has homologous targeting capabilities, allowing for the preparation of target tumor cells. The borate ester bond between selenium nanoparticles (SSe) and baicalein (BE) is pH-sensitive and can break under acidic conditions in the tumor microenvironment to achieve the targeted release of BE at the tumor site. Moreover, SSe further enhances the antitumor effect of BE by increasing the production of ROS in tumor cells. Transmission electron microscopy (TEM) images and dynamic light scattering (DLS) showed that the ACM-SSe-BE had a particle size of approximately 155 ± 2 nm. FTIR verified the successful coupling of SSe and BE. In vitro release experiments indicated that the cumulative release of ACM-SSe-BE at pH 5.5 after 24 h was 69.39 ± 1.07%, which was less than the 20% release at pH 7.4, confirming the pH-sensitive release of BE in ACM-SSe-BE. Cell uptake experiments and in vivo imaging showed that ACM-SSe-BE had good targeting ability. The results of MTT, flow cytometry, Western blot, and cell immunofluorescence staining demonstrated that ACM-SSe-BE promoted A549 cell apoptosis and inhibited cell proliferation. The in vivo antitumor results were consistent with those of the cell experiments. These results clearly suggested that ACM-SSe-BE will be a promising bionic nanosystem for the treatment of nonsmall cell lung cancer.

HDAC3 genetic and pharmacologic inhibition radiosensitizes fusion positive rhabdomyosarcoma by promoting DNA double-strand breaks

Radiotherapy (RT) plays a critical role in the management of rhabdomyosarcoma (RMS), the prevalent soft tissue sarcoma in childhood. The high risk PAX3-FOXO1 fusion-positive subtype (FP-RMS) is often resistant to RT. We have recently demonstrated that inhibition of class-I histone deacetylases (HDACs) radiosensitizes FP-RMS both in vitro and in vivo. However, HDAC inhibitors exhibited limited success on solid tumors in human clinical trials, at least in part due to the presence of off-target effects. Hence, identifying specific HDAC isoforms that can be targeted to radiosensitize FP-RMS is imperative. We, here, found that only HDAC3 silencing, among all class-I HDACs screened by siRNA, radiosensitizes FP-RMS cells by inhibiting colony formation. Thus, we dissected the effects of HDAC3 depletion using CRISPR/Cas9-dependent HDAC3 knock-out (KO) in FP-RMS cells, which resulted in Endoplasmatic Reticulum Stress activation, ERK inactivation, PARP1- and caspase-dependent apoptosis and reduced stemness when combined with irradiation compared to single treatments. HDAC3 loss-of-function increased DNA damage in irradiated cells augmenting H2AX phosphorylation and DNA double-strand breaks (DSBs) and counteracting irradiation-dependent activation of ATM and DNA-Pkcs as well as Rad51 protein induction. Moreover, HDAC3 depletion hampers FP-RMS tumor growth in vivo and maximally inhibits the growth of irradiated tumors compared to single approaches. We, then, developed a new HDAC3 inhibitor, MC4448, which showed specific cell anti-tumor effects and mirrors the radiosensitizing effects of HDAC3 depletion in vitro synergizing with ERKs inhibition. Overall, our findings dissect the pro-survival role of HDAC3 in FP-RMS and suggest HDAC3 genetic or pharmacologic inhibition as a new promising strategy to overcome radioresistance in this tumor.

Light-activated hypoxia-sensitive biomimetic decoy efficiently cascading photodynamic-chemo therapy for breast cancer

The hypoxic microenvironment within the tumor microenvironment of breast cancer imposes a challenge in overcoming chemotherapy resistance. In this investigation, we designed a novel strategy utilizing a light-controlled cascade targeting nanomedicine specifically tailored for enhanced immune therapy of breast cancer. Albumin nanoparticle was achieved by crosslinking, followed by loading TPZ and Ce6, and subsequent modification to enable selective binding with CD44 hyaluronic acid to form nanomedicine. Encouragingly, it was demonstrated the remarkable ability of the nanomedicine to effectively internalize into cellular entities, thereby inducing apoptosis in 4T1 cells efficiently in vitro when exposed to light irradiation. In vivo assessments showcased the exceptional aptitude of the nanomedicine not only for preferential accumulation within tumor tissues, but also for substantial suppression of tumor growth. Immune mechanisms have shown that nanomedicine treatment promoted the maturation of DCs in vivo, enhanced the proportion of CD8+ T cells in the spleen and tumor, and simultaneously upregulated the ratio of M1 macrophages favorable for anti-tumor effects. These outcomes collectively advance a fresh perspective for the clinical breast cancer therapy.

PD-1 controls differentiation, survival, and TCR affinity evolution of stem-like CD8+ T cells.

Stem-like progenitors are a critical subset of cytotoxic T cells that self-renew and give rise to expanded populations of effector cells critical for successful checkpoint blockade immunotherapy. Emerging evidence suggests that the tumor-draining lymph nodes can support the continuous generation of these stem-like cells that replenish the tumor sites and act as a critical source of expanded effector populations, underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Using advanced 3D multiplex immunofluorescence imaging, here we identified antigen-presentation niches in tumor-draining lymph nodes that support the expansion, maintenance, and affinity evolution of a unique population of TCF-1+PD-1+SLAMF6 hi stem-like CD8+ T cells. Our results show that contrary to the prevailing view that persistent TCR signaling drives terminal effector differentiation, prolonged antigen engagement well beyond the initial priming phase sustained the proliferation and self-renewal of these stem-like T cells in vivo . The inhibitory PD-1 pathway plays a central role in this process by mediating the fine-tuning of TCR and co-stimulatory signal input that enables selective expansion of high affinity TCR stem-like clones, enabling them to act as a renewable source of high affinity effector cells. PD-1 checkpoint blockade disrupts this fine tuning of input signaling, leading to terminal differentiation to the effector state or death of the most avid anti-tumor stem-like cells. Our results thus reveal an unexpected relationship between TCR ligand affinity recognition, a key negative feedback regulatory loop, and T cell stemness programming. Furthermore, these findings raise questions about whether anti-PD-1 checkpoint blockade during cancer immunotherapy provides a short-term anti-tumor effect that comes at the cost of diminishing efficacy due to progressive loss of these critical high affinity stem-like precursors.

Targeting tumor-associated macrophage-derived CD74 improves efficacy of neoadjuvant chemotherapy in combination with PD-1 blockade for cervical cancer

BackgroundCervical cancer has the second-highest mortality rate among malignant tumors of the female reproductive system. Immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) blockade are promising therapeutic...

Oral Administration of Carotenoid-Rich Dunaliella salina Powder Inhibits Colon Carcinogenesis via Modulation of Wnt/β-catenin Signaling Cascades in a Rat Model.

The present study aims to investigate the oral therapeutic and molecular role of carotenoid-rich Dunaliella salina powder (DSP) against 1,2-dimethylhydrazine (DMH)-triggered colon carcinogenesis. In this study, thirty six male Wistar rats were categorized into six distinct groups (G1-G6): G1 group with no intervention, G2 group received only DSP (1000mg/kg), G3 group received only DMH carcinogen (20mg/kg), and G4-G6 group received both DMH and DSP at various phases (pre-initiation, post-initiation and entire phases) for 32weeks. Body weight, tumor incidence, tumor volume, histopathological examination, antioxidants, and detoxification enzymes activities were analyzed in the experimental rats. In addition, the protein expression profile of components involved in the Wnt/β-catenin signaling pathway was determined by western blot analysis. Matrix metalloproteinases (MMP-7 and MMP-9), proliferation marker (PCNA), and pro-apoptotic (Bcl-2 and Bax) proteins were analyzed using immunohistochemistry. Colorimetric assay was used to determine the levels of anti-inflammatory (iNOS and COX-2) and apoptotic proteins (Caspase-3 and Caspase-9). Results showed that concomitant administration of DSP with DMH significantly reduced tumor progression and prevented colon carcinogenesis in rats. However, treatment with DSP before or after DMH exposure did not significantly prevent colon carcinogenesis. DMH and DSP treatment group showed increased activities of antioxidant enzymes with significant reduction in the oxidative stress. Additionally, the detoxification enzymes and colonic histopathology of those rats were restored to that of control rats. The administration of DSP to rats exposed to DMH exhibited antitumor effects via inhibition of the Wnt/β-catenin signaling pathway with induced apoptosis through the Bcl-2/Bax/caspases signaling cascades. Moreover, the same group also showed significant anti-inflammatory activity via regulating iNOS and COX-2 biomarkers. Our findings revealed molecular chemopreventive activity of carotenoid-rich DSP through regulating Wnt/beta-catenin and intrinsic apoptotic pathways. Thus, DSP is propound to function as a potent antioxidant, anti-proliferative, and anti-inflammatory therapeutic agent against colon carcinogenesis.

Anti-tumor effect and hepatotoxicity mechanisms of psoralen.

In recent years, natural products have gradually become an important source for new drug development due to their advantages of multi-components, multi-targets, and good safety profiles. Psoralen, a furanocoumarin compound extracted from the traditional Chinese medicine psoralea corylifolia, is widely distributed among various plants. It has attracted widespread attention in the research community due to its pharmacological activities, including antitumor, anti-inflammatory, antioxidant, and neuroprotective effects. Studies have shown that psoralen has broad spectrum anti-tumor activities, offering resistance to malignant tumors such as breast cancer, liver cancer, glioma, and osteosarcoma, making it a natural, novel potential antitumor drug. Psoralen mainly exerts its antitumor effects by inhibiting tumor cell proliferation, inducing apoptosis, inhibiting tumor cell migration, and reversing multidrug resistance, presenting a wide application prospect in the field of antitumor therapy. With the deepening research on psoralea corylifolia, its safety has attracted attention, and reports on the hepatotoxicity of psoralen have gradually increased. Therefore, this article reviews recent studies on the mechanism of antitumor effects of psoralen and focuses on the molecular mechanisms of its hepatotoxicity, providing insights for the clinical development of low-toxicity, high-efficiency antitumor drugs and the safety of clinical medication.

Optimizing the fucoidan extraction using Box-Behnken Design and its potential bioactivity

Fucoidan is a sulfated polysaccharide that occurs naturally in the cell wall of brown seaweeds and has substantial biological efficacy. Optimizing the extraction of fucoidan from different brown seaweeds was the primary goal of this research. The optimization of fucoidan extraction was applied on the brown macroalga Turbinaria turbinata using a Box-Behnken Design (BBD) to inspect the impacts of different pH (3, 5, 7), temperature (70, 80, 90 °C) and extraction duration (60, 120, 180 min) on both the yield and sulfate content of fucoidan. The optimized parameters recorded to maximize the fucoidan yield and its sulfate content were a pH of 3.44 and a temperature of 82.26 °C for 60 min. The optimal conditions obtained from BBD were used for fucoidan extraction from T. turbinata, Sargassum cinereum, Padina pavonica, and Dictyota dichotoma. The highest average of fucoidan yield was derived from P. pavonica (40.76 ± 4.04 % DW). FTIR, 1H NMR, and HPLC were used to characterize extracted fucoidan. The extracted fucoidan's Physical characteristics, biochemical composition, antioxidant potential, antitumor effect against breast cancer cells (MCF-7), and antimicrobial and anticoagulant activity were assessed. The extracted fucoidan from D. dichotoma, followed by that extracted from S. cinereum, which had the highest sulphate content, depicted the highest antioxidant, anticancer, and anticoagulant activities. Fucoidan has demonstrated a strong antimicrobial action against some pathogenic microorganisms; Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, and Candida albicans. The anticoagulant properties of fucoidan from D. dichotoma were stronger than those of fucoidan from S. cinereum, T. turbinata, and P. pavonica due to its higher sulphate content. These findings could be used for various biomedical applications to improve the pharmaceutical industry.

Discovery of Novel Imidazo[1,2-a]pyridine-Based HDAC6 Inhibitors as an Anticarcinogen with a Cardioprotective Effect.

Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.

Insight into the nuclear distribution patterns of conidia and the asexual life cycle of Polyporus umbellatus

P. umbellatus sclerotium is a traditional Chinese medicine that is widely utilized in China, Korea, Japan, and other countries due to its diverse medicinal activities, such as diuretic, antitumor, anticancer, and immune system enhancement effects. Conidia, which are common asexual spores in various fungi, are not universally present in Polyporus species. In this study, the asexual life cycle of P. umbellatus was elucidated. Conidia, i.e. arthorconidia, were produced by both dikaryotic and monokaryotic strains. In the dikaryotic strain, binucleate, uninucleate, and nuclei-free conidia were identified with proportions of 67.9 %, 12.4 %, and 19.7 %, respectively. Conversely, the monokaryotic strain did not produce binucleate conidia. This discrepancy suggests that binucleate spores are heterokaryons, while uninucleate spores are homokaryons. Clamp connections were observed in dikaryotic hyphae, but were absent in monokaryotic hyphae. Monokaryotic strains were obtained from conidia of the dikaryotic strain. Additionally, mating types were determined through pairing tests, and successful crossbreeding occurred between monokaryotic strains derived from conidia and basidiospores from different strains. This study introduced the first crossbreeding strategy for P. umbellatus.

Multi-omics reveals bufadienolide Q-markers of Bufonis Venenum based on antitumor activity and cardiovascular toxicity in zebrafish

BackgroundBufonis Venenum (BV) is a traditional animal-based Chinese medicine with therapeutic effects against cancer. However, its clinical use is significantly restricted due to associated cardiovascular risks. BV's value in China's market is typically assessed based on “content priority,” focusing on indicator components. However, these components of BV possess both antitumor activity and toxicity, and the correlation between the antitumor activity and toxicity of BV has not yet been elucidated. PurposeThis study employs an integrated multi-omics approach to identify bufadienolide Q-markers and explore the correlation between BV's antitumor activity and toxicity. The aim is to establish a more comprehensive method for BV's quality. MethodsNormal zebrafish and HepG2 xenograft zebrafish were chosen as activity and toxicity evaluation models. Ultra-high performance liquid chromatography (UHPLC) coupled with a linear ion trap orbitrap (LTQ-Orbitrap) mass spectrometry was used to quantify eight batches of BV and key “toxic and effective” components were screened out. Transcriptomic and metabolomic analyses were performed to elucidate the regulatory mechanisms underlying the antitumor activity and cardiovascular toxicity of the key components in BV. ResultsEight key “toxic and effective” compounds were identified: resibufogenin, cinobufagin, arenobufagin, bufotalin, bufalin, gamabufotalin, desacetylcinobufagin, and telocinobufagin. The findings showed that bufalin and cinobufagin interfered with calcium homeostasis through CaV and CaSR, induced cardiotoxicity, and upregulated CASP9 to activate myocardial cell apoptosis. However, desacetylcinobufagin exhibited greater potential in terms of anti-tumor effects. Combining the results of untargeted and targeted metabolomics revealed that desacetylcinobufagin could have a callback effect on differential lipids and correct abnormal energy and amino acid metabolism caused by cancer, similar to cinobufagin and bufalin. Microscale thermophoresis (MST) ligand binding measurements also showed that the binding of desacetylcinobufagin to GPX4 has a more potent ability to induce ferroptosis in tumor cells compared to cinobufagin. ConclusionAn innovative evaluation method based on the zebrafish was developed to investigate the relationship between the toxicity and efficacy of BV. This study identified toxicity and activity Q-markers and explored the mechanism between the two effects of BV. The research data could offer valuable insights into the efficacy of BV. Additionally, desacetylcinobufagin, an active ingredient with low toxicity, was found to enhance the quality of BV.

Remodeling the hepatic immune microenvironment and demolishing T cell traps to enhance immunotherapy efficacy in liver metastasis

Immune checkpoint inhibitors (ICIs) exhibit compromised therapeutic efficacy in many patients with advanced cancers, particularly those with liver metastases. Much of this incapability can be ascribed as an irresponsiveness resulting from the “cold” hepatic tumor microenvironment that acts as T cell “traps” for which there currently lack countermeasures. We report a novel nanomedicine that converts the hepatic immune microenvironment to a “hot” phenotype by targeting hepatic macrophage-centric T cell elimination. Using the nanomedicine, composed of KIRA6 (an endothelium reticulum stress inhibitor), α-Tocopherol nanoemulsions, and anti-PD1 antibodies, we found its potency in murine models of orthotopic colorectal tumors and hepatic metastases, restoring immune responses and enhancing anti-tumor effects. A post-treatment scrutiny of the immune microenvironment landscape in the liver reveals repolarization of immunosuppressive hepatic macrophages, upregulation of Th1-like effector CD4+ T cells, and rejuvenation of dendritic cells along with CD8+ T cells. These findings suggest adaptations of liver-centric immune milieu modulation strategies to improve the efficacy of ICIs for a variety of “cold” tumors and their liver metastases.

Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.

Epigenetic regulation of NKG2D ligand and the rise of NK cell-based immunotherapy for cancer treatment.

Epigenetic modifications influence gene expression and effects cancer initiation and progression. Therefore, they serve as diagnostic and prognostic biomarkers and potential therapeutic targets. Natural Killer (NK) cells, integral to the innate immune system, exhibit anti-tumor effect by recognizing and eliminating cancerous cells through the balance of activating and inhibitory ligands. Understanding the epigenetic regulation of NK cell ligands offers insights into enhancing NK cell-mediated tumor eradication. This review explores the epigenetic modifications governing the expression of activating NKG2D ligands and discusses clinical trials investigating NK cell-based immunotherapies, highlighting their potential as effective cancer treatment strategies. Case studies examining the safety and effectiveness of NK cell therapies in different cancer types, such as acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC), demonstrate promising outcomes with minimal toxicity. These findings underscore the therapeutic prospects of epigenetic modulation of NKG2D ligands and NK cell-based immunotherapies as effective cancer treatment strategies. Future research in the advancement of personalized medicine approaches and novel combination therapies with NK cell will further improve treatment outcomes and provide new therapeutic options for treating patients with various types of cancer.

The use of matrine to inhibit osteosarcoma cell proliferation via the regulation of the MAPK/ERK signaling pathway.

Matrine is an alkaloid extracted from Sophorus beans of the legume family, and it has significant effects and a variety of pharmacological activities. Osteosarcoma(OS) is a common malignant bone tumor that is characterized by high incidence and rapid progression. There have been some preliminary studies on the therapeutic effect of matrine on OS, but the specific mechanism remains unclear. The aim of this study was to investigate the antitumor effect of matrine on HOS cells and the underlying molecular mechanism. The effects of matrine on the proliferation, apoptosis and cell cycle progression of HOS cells were determined by CCK-8 assay, TUNEL assay and flow cytometry in vitro. Wound healing and Transwell invasion assays were used to observe the effect of matrine on the migration and invasion of HOS cells. The mechanism underlying the antitumor effect of matrine on HOS cells was investigated by Western blotting. Matrine significantly inhibited HOS cell proliferation, promoted HOS cell apoptosis, and arrested HOS cells in the G1 phase of the cell cycle. Both wound healing and Transwell invasion assays showed that matrine inhibited HOS cell migration and invasion. Western blotting results showed that matrine inhibited the activation of the MAPK/ERK signaling pathway. We found that matrine also downregulated Bcl-2 expression, which may be related to protein synthesis inhibition. Matrine can inhibit the proliferation of HOS cells, arrest HOS cells in the G1 phase, and promote HOS cell apoptosis through the MAPK/ERK signaling pathway.

Curcumin Inhibits the Development of Pancreatic Cancer by Targeting the circ_0079440/miR-522-3p/EIF4A1 Pathway.

Pancreatic cancer (PC) is a common gastrointestinal cancer with high invasiveness and high mortality. Curcumin is a natural polyphenol with anti-tumor activity against different cancers, including PC. Curcumin has been verified to mediate the expression of circular RNAs (circRNAs) to inhibit tumor development. This study aimed to explore the function and regulatory mechanism of curcumin on circ_0079440 in PC. PC cells were treated with different concentrations of curcumin (0, 5, 10 or 15 μM) for 24 h. Gene expression in PC cells and tissues was detected using RT-qPCR. Cell malignant phenotypes were determined by functional assays. The levels of EMT-related proteins were tested using western blot. RNA interaction was determined using RNA pulldown assay, luciferase reporter assay and RIP assay. The results showed that curcumin suppressed cell proliferative, migratory, and invasive capabilities, and weakened epithelial-mesenchymal transition (EMT) in a concentration-dependent way. Circ_0079440 was expressed at a high level in PC and its level was reduced via curcumin administration in PC cells. Rescue assays showed that circ_0079440 overexpression reversed the suppressive effects of curcumin on PC cell malignant phenotypes. Furthermore, in the xenograft mouse models, curcumin treatment inhibited tumor growth and metastasis, and circ_0079440 upregulation reversed the function of curcumin. Additionally, circ_0079440 was revealed to bind to miR-522-3p to upregulate eukaryotic initiation factor 4A1 (EIF4A1) expression in PC cells. EIF4A1 expression was also downregulated by curcumin, and EIF4A1 overexpression abolished the suppressive functions of curcumin. Moreover, EIF4A overexpression or miR-522-3p inhibition counteracted the anti-tumor effects of circ_0079440 depletion on PC development. To sum up, curcumin suppresses PC development by targeting the circ_0079440/miR-522-3p/EIF4A1 pathway, which might provide novel therapeutic targets for treatment of PC.

Functional exosomes modified with chitosan effectively alleviate anthracycline-induced cardiotoxicity

Anthracyclines belong to a class of anti-tumor antibiotics, and their severe cardiotoxicity significantly limits their clinical use. Exosomes play key roles in intercellular communication, characterized by high biocompatibility and specific tissue and organ homing effects. In this study, doxorubicin, an anthracycline anticancer drug widely used in clinical chemotherapy, was selected as a model drug. To address the significant cardiotoxicity associated with doxorubicin, tumor exosomes are utilized as drug carriers. The homing effect of autologous exosomes enhances drug uptake by tumor cells and reduces cardiotoxicity. To enhance the stability of exosomes, improve therapeutic effectiveness, and reduce toxic side effects, chitosan was utilized to modify the surface of exosomes. Chitosan has a specific anti-tumor effect because it can target the CD44 receptor of tumor stem cells and interact with tumor cells through charge adsorption. Through in vitro cell experiments, in vivo pharmacokinetic experiments, and an in situ ectopic nude mouse tumor model, the study demonstrated that chitosan-modified tumor exosomes significantly alleviated the severe cardiotoxicity of doxorubicin, while also showing remarkable anti-tumor efficacy. This study introduces a novel approach to reduce the adverse side effects of anthracycline chemotherapeutic drugs and presents a highly promising nanocarrier delivery system.

Revealing the impact of modified modules flexibility on gemcitabine prodrug nanoassemblies for effective cancer therapy

Prodrug nanoassemblies combine the advantages of prodrug strategies and nanotechnology have been widely utilized for delivering antitumor drugs. These prodrugs typically comprise active drug modules, response modules, and modification modules. Among them, the modification modules play a critical factor in improving the self-assembly ability of the parent drug. However, the impact of the specific structure of the modification modules on prodrug self-assembly remains elusive. In this study, two gemcitabine (GEM) prodrugs are developed using 2-octyl-1-dodecanol (OD) as flexible modification modules and cholesterol (CLS) as rigid modification modules. Interestingly, the differences in the chemical structure of modification modules significantly affect the assembly performance, drug release, cytotoxicity, tumor accumulation, and antitumor efficacy of prodrug nanoassemblies. It is noteworthy that the prodrug nanoassemblies constructed with flexible modifying chains (OD) exhibit improved stability, faster drug release, and enhanced antitumor effects. Our findings elucidate the significant impact of modification modules on the construction of prodrug nanoassemblies.

An engineered self-biomineralized oncolytic adenovirus induces effective antitumor immunity and synergizes with immune checkpoint blockade.

Oncolytic adenoviruses (oADV) are promising cancer treatment agents. However, in vivo hepatic sequestration and the host immunological response against the agents limit the therapeutic potential of oADVs. Herein, we present a combined, rational design method for improving oADV infection efficiency, immunogenicity, and treatment efficacy by self-biomineralization. We integrated the biomimetic nucleopeptide W6p into the capsid of oADV using reverse genetics, allowing calcium phosphate mineralization to be biologically induced on the surface of oADV under physiological conditions, resulting in a mineral exterior. This self-biomineralized, modified oADV (oADV-W6-CaP) enhanced infection efficiency and therapeutic efficacy in coxsackie and adenovirus receptor (CAR)-negative cancer cells while protecting them against neutralization by pre-existing neutralizing antibodies. In subcutaneous mouse tumor models, systemic injection of oADV-W6-CaP demonstrated improved antitumor effectiveness, which was associated with increased T-cell infiltration and CD8+ T-cell activation. In addition, the anticancer immune response elicited by oADV-W6-CaP was dependent on CD8+ T cells, which mediated long-term immunological memory and systemic antitumor immunity against the same tumor. Finally, the addition of PD-1 or CD47 inhibition boosted the anticancer effects of oADV-W6-CaP and raised the rate of complete tumor clearance in tumor-bearing animals. The self-biomineralized oADV shifted the suppressive tumor microenvironment from a "cold" state to a "hot" state and synergized with immune checkpoint blockade to exert outstanding tumoricidal effects, demonstrating promising potential for cancer immunotherapy.