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Esophageal cancer remains a formidable challenge in oncology, characterized by its poor prognosis and limited therapeutic options. Recent investigations have unveiled the potential of repurposing existing drugs for cancer treatment. Notably, etomidate, an anesthetic agent traditionally used for inducing general anesthesia, has emerged as a promising candidate demonstrating significant anticancer properties across various tumor types. The present study aims to investigate the effects of etomidate on esophageal carcinoma cells, with a specific focus on its ability to modulate the PI3K/AKT signaling pathway and inhibit tumor proliferation. This study employed both in vitro and in vivo methodologies to assess the effects of etomidate on esophageal cancer cells. In vitro experiments evaluated the effects of etomidate on cell proliferation, migration, invasion, and glycolytic processes. An in vivo xenograft mouse model was established to investigate the therapeutic potential of etomidate on tumor growth and assess its impact on the PI3K/AKT signaling pathway in a physiologically relevant context. Etomidate demonstrated a significant inhibitory effect on the proliferation, migration, invasion, and glycolytic capacity of esophageal cancer cells. This multifaceted suppression of tumorigenic properties was closely associated with the inhibition of the PI3K/AKT pathway, as evidenced by reduced phosphorylation levels of PI3K and AKT. In vivo studies using a murine model of esophageal cancer corroborated these findings. Etomidate administration resulted in a substantial reduction in tumor volume and mass, accompanied by increased apoptotic activity and the inhibition of the PI3K/AKT pathway within the tumor tissue. This study demonstrates etomidate’s potent inhibition of esophageal cancer progression through suppression of the PI3K/AKT pathway. These promising results warrant further clinical investigation of etomidate as a potential therapeutic strategy for esophageal cancer. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer among women worldwide, and adjuvant radiotherapy (RT) following tumor removal is one of the most commonly used treatments for breast cancer. However, the high risk of tumor recurrence and inevitable radiation skin injury after RT remain fatal problems, seriously challenging the patient's postoperative rehabilitation. Herein, a multifunctional poly (lipoic acid)-based hydrogel is constructed through one-step heating the mixture of α-lipoic acid (LA)/arginine (Arg)/silk fibroin (SF), without introducing any non-natural molecules. The multiple synergistic interactions among LA, Arg, and SF not only enhance the solubilization of LA in aqueous systems but also stabilize poly(lipoic acid) through strong salt bridge hydrogen bonds and ionic hydrogen bonds. Intriguingly, the LA-based surfactant induced β-sheet transformation of SF can further modulate the bulk strength of the hydrogel. Regulating the content of LA in hydrogels not only allows efficient control of hydrogel bioactivity but also enables the evolution of hydrogels from injectable forms to adhesive patches. Based on the different biological activities and forms of hydrogels, they can be implanted internally or applied externally on the mice's skin, achieving simultaneous prevention of tumor recurrence post-surgery and assistance in treating radiation-induced skin damage after radiotherapy.

Simple Summary: Green healthcare relates to using naturally derived sources as medicines to treat and personalize treatments for various diseases. Cancer is one primary global health concern due to its rapid evolution and high prevalence, especially lung cancer. Cinobufagin (CB), a bufadienolide derived primarily from the parotid glands of frogs, has shown promise in combating lung cancer. Our objective with this systematic review is to synthesize the current evidence on CB's effects against lung cancer, focusing on its mechanisms of action, efficacy, and potential clinical implications. Our results indicated that CB reduces lung cancer tumor growth via increased apoptosis by reducing cancer cells' viability. In addition, CB also has impacted migration and invasion across multiple lung cancer cell lines and xenograft models. The molecular pathways involved Bcl-2, Bax, cleaved caspases, caveolin-1, FLOT2, Akt, STAT3, and FOXO1. CB achieved these effects with minimal toxicity. Cinobufagin (CB), a bufadienolide, has shown promising potential as an anticancer agent, particularly in combating lung cancer. This systematic review synthesizes preclinical evidence on CB's effects against lung cancer, focusing on its mechanisms of action, efficacy, and potential clinical implications. We analyzed data from various preclinical studies involving both in vitro cell line models and in vivo animal models. The reviewed studies indicate that CB effectively reduces cell viability, induces apoptosis, and inhibits cell proliferation, migration, and invasion across multiple lung cancer cell lines and xenograft models. Specifically, CB was found to decrease cell viability and increase apoptosis in lung cancer cells by modulating key molecular pathways, including Bcl-2, Bax, cleaved caspases, caveolin-1, FLOT2, Akt, STAT3, and FOXO1. In vivo studies further demonstrated significant inhibition of tumor growth with minimal toxicity. However, limitations include reliance on in vitro models, which may not fully represent in vivo tumor dynamics, and a lack of long-term safety data. The studies also vary in their methodologies and cell line models, which may not accurately encompass all lung cancer subtypes or predict human responses. Despite these limitations, CB's ability to target specific molecular pathways and its promising results in preclinical models suggest it could be a valuable addition to lung cancer treatment strategies. Our review suggests further clinical trials to validate its efficacy and safety in humans. Future research should explore combination therapies and optimize delivery methods to enhance clinical outcomes. [ABSTRACT FROM AUTHOR]

Anti-CTLA-4 antibodies faced challenges due to frequent adverse events and limited efficacy, which spurred the exploration of next-generation CTLA-4 therapeutics to balance regulatory T cells (Tregs) depletion and CD8 T cells activation. CCR8, identified primarily on tumor-infiltrating Tregs, has become a target of interest due to the anti-tumor effects demonstrated by CCR8 antibody-mediated Tregs depletion. Single-cell RNA sequencing analysis reveals that CCR8-positive Tregs constitute a small subset, with concurrent expression of CCR8 and CTLA-4. Consequently, we proposed a novel bispecific antibody targeting CCR8 and CTLA-4 that had the potential to enhance T cell activation while selectively depleting intratumor Tregs. The candidate molecule 2MW4691 was developed in a tetravalent symmetric format, maintaining a strong binding affinity for CCR8 while exhibiting relatively weaker CTLA-4 binding. This selective binding ability allowed 2MW4691 to target and deplete tumor-infiltrating Tregs with higher specificity. In vitro assays verified the antibody’s capacity for antibody-dependent cellular cytotoxicity (ADCC) to Tregs with high level of CTLA-4 expression, but not CD8 T cells with relatively low level of CTLA-4 on cell surface. Also, 2MW4691 inhibited the CTLA-4 pathway and enhanced T cell activation. The in vivo therapeutic efficacy of 2MW4691 was further demonstrated using hCCR8 or hCTLA-4 humanized mouse models and hCCR8/hCTLA-4 double knock-in mouse models. In cynomolgus monkeys, 2MW4691 was well-tolerated, exhibited the anticipated pharmacokinetic profile, and had a minimal impact on the peripheral T cell population. The promising preclinical results supported the further evaluation of 2MW4691 as a next-generation Treg-based therapeutics in clinical trials. [ABSTRACT FROM AUTHOR]

The root cause of metabolic chronic syndrome, malignant tumors, and viral/bacterial infections is unconventional biomolecular-recognition-mediated cascade reactions, or the overexpression or suppression of these reactions. Molecularly imprinted polymers (MIPs) are usually obtained by copolymerization of functional and crosslinking monomers in the presence of template molecules. Upon removing the template molecules, the cavities left in the polymer can specifically bind to the targets, which underlies their intervention activities. MIPs can participate in various biological processes without negative interference, such as targeted drug delivery, blocking pathogenic signaling pathways and constructing functional signal connections, thereby controlling cell fate by regulating their proliferation, migration and apoptosis fate behaviors. Molecular imprints, which are crosslinked architectures containing specific molecular recognition cavities for targeting compounds, have recently transitioned from in vitro diagnosis to in vivo treatment. In current application scenarios, it has become an important topic to create new biomolecular recognition pathways through molecular imprinting, thereby inhibiting the pathogenesis and regulating the development of diseases. This review starts with a pathological analysis, mainly focusing on the corresponding artificial enzymes, enzyme inhibitors and antibody mimics with enhanced functions that are created by molecular imprinting strategies. Recent advances are highlighted in the use of molecular imprints as tailor-made nanomedicines for the prevention of three major diseases: metabolic syndrome, cancer, and bacterial/viral infections. [ABSTRACT FROM AUTHOR]

Gastric cancer is a prevalent malignant tumor worldwide, posing challenges due to its poor prognosis and limited treatment options. Cancer stem cells (CSCs) were demonstrated as a subset of cancer cells responsible for tumor initiation and progression, and their inherent resistance to conventional chemotherapy and radiotherapy critically contributes to tumor recurrence and metastasis. Promoting the eradication of cancer stem cells is crucial for enhancing the efficacy of cancer treatments. This study introduces a novel therapeutic strategy utilizing polyhedral magnetic nanoparticles (PMNPs) functionalized with CD44 antibodies and cell-penetrating peptides (CPPs) to improve uptake by gastric cancer stem cells (MCSCs). PMNPs, synthesized via thermal decomposition, exhibited a diameter of 90 nm ± 9 nm and a saturation magnetization of 79.9 emu/g. Functionalization enhanced their uptake capabilities. Under a rotating magnetic field (RMF) of 15 Hz, PMNPs disrupted cellular structure, leading to apoptosis and ferroptosis in MCSCs. The in vitro studies showed significant reduction in MCSCs viability, while in vivo studies demonstrated tumor growth suppression with minimal side effects and high biocompatibility. This work presents a novel strategy for designing magnetic nanoparticles to mechanically destroy cancer stem cells, offering a more efficient and safety treatment option for gastric cancer. [Display omitted] • Gastric cancer stem cells (MCSCs) serves as a linchpin in the genesis and progression of gastric cancer. • This dual functionalization enhances the uptake of polygonal magnetic nanoparticles (PMNPs) by gastric cancer stem cells. • Under a rotating magnetic field of 15 Hz, PMNPs induced apoptosis and ferroptosis in MCSCs by disrupting cellular structures. • The PMNPs system showed remarkable efficacy in inhibiting tumor growth in vivo and has significant biocompatibility. [ABSTRACT FROM AUTHOR]

Objective: This research aims to improve the bioavailability and anti-hepatocellular carcinoma (HCC) efficacy of Ginsenoside Rg3 by modification with poly (lactic acid hydroxyacetic acid)-poly(ethylene glycol) (PLGA-PEG). Methods: PLGA-PEG-Rg3 was obtained by emulsification and evaluated it physiochemical characterization by FTIR, SEM, laser particle-size analyzer and HPLC. The effect of the PLGA-PEG-Rg3 and Rg3 on HepG2 cells was compared in vitro studies, including cell proliferation, transwell and a series of apoptosis detection, and in-situ HCC model. Results: The PLGA-PEG-Rg3 were 122 nm in size and 0.112 in polydispersity index with sustained release profile in vitro. Compared to Rg3, PLGA-PEG-Rg3 was more effective in suppressing HepG2 growth and inducing apoptosis by the mitochondrial apoptosis pathway in vitro. And PLGA-PEG modification enhanced the liver-targeting ability and drug circulation time of Rg3 in vivo, resulting in PLGA-PEG-Rg3 possessing superior performance in inhibiting tumor growth and prolonging the survival time of tumor-bearing mice than Rg3. Conclusions: Overall, these results showed PLGA-PEG-Rg3 enhanced the anti-tumor effect of Rg3 in HCC. [ABSTRACT FROM AUTHOR]

This article examines the efficacy of Trametes versicolor-derived polysaccharide in tumor inhibition and modulation of immune response. The main objective was to evaluate the impact of the polysaccharide in reducing tumor growth and regulating immune functions in experimental models. In vitro and in vivo assays were reviewed, where controlled doses of the polysaccharide were administered to mice with induced tumors, and changes in tumor size and immunological parameters, such as T cell activity and cytokine production, were analyzed. The results showed that Trametes versicolor polysaccharide significantly reduced tumor size and positively modulated the immune response, increasing T cell cytotoxic activity and enhancing proinflammatory cytokine production. These findings suggest that the polysaccharide has remarkable potential as a therapeutic agent in oncology and immunotherapy, contributing to both the reduction of tumor growth and the optimization of the immune response. [ABSTRACT FROM AUTHOR]

The repair and reconstruction of large bone defects after bone tumor resection is still a great clinical challenge. At present, orthopedic implant reconstruction is the mainstream treatment for repairing bone defects. However, according to clinical feedback, local tumor recurrence and nonunion of bone graft are common reasons leading to the failure of bone defect repair and reconstruction after bone tumor resection, which seriously threaten the physical and mental health of patients. On this basis, here the self-developed low modulus Ti-12Mo-10Zr alloy (TMZ) was chosen as substrate material. To improve its biological activity and osteointegration, calcium, oxygen, and phosphorus co-doped microporous coating was prepared on TMZ alloy by microarc oxidation (MAO). Then, black phosphorus (BP) nanosheets were incorporated onto MAO treated TMZ alloy to obtain multifunctional composites. The obtained BP-MAO-TMZ implant exhibited excellent photothermal effects and effective ablation of osteosarcoma cancer cells under the irradiation of 808 nm near infrared laser, while no photothermal or therapeutic effects were observed for TMZ alloy. Meanwhile, the structure/component bionic coating obtained after MAO treatment as well as the P-driven in situ biomineralization performance after incorporation of BP nanosheets endowed BP-MAO-TMZ implant with synergistic promoting effect on MC3T3-E1 osteoblasts' activity, proliferation and differentiation ability. This study is expected to provide effective clinical solutions for problems of difficult bone regeneration and tumor recurrence after tumor resection in patients with bone tumors and to solve a series of medical problems such as poor prognosis and poor postoperative quality of patients life with malignant bone tumors. [ABSTRACT FROM AUTHOR]

Abstract Serous ovarian cancer is one of the major causes of cancer related death among women worldwide. The advanced diagnosis worsens the prognosis of patients with serous ovarian cancer. The immune system has an important impact on the progression of ovarian cancer. Herein, we aimed to establish an immune related prognostic signature to assist in the early diagnosis, treatment, and prognostic evaluation of patients with serous ovarian cancer. Multiple public data sets and immune related genes were obtained from various online public databases, and immune related prognostic signatures were developed through differential expression analysis, univariate Cox proportional hazard regression analysis, and the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model. The nomogram model, Kaplan–Meier survival curve analysis, receiver operating characteristic (ROC) curve analysis, and decision curve analysis showed that this signature had a good prediction potential. In conclusion, an immune related signature with good prediction efficiency was established through systematic bioinformatics analysis, which may play a tumor inhibition role by affecting the abundance of activated dendritic cells.

Human epidermal growth factor receptor 2 (HER2) is considered an ideal antibody–drug conjugate (ADC) target because the gene is overexpressed in many tumors compared to normal tissues. Multiple anti-HER2 ADCs conjugated with different toxic payloads bring benefits to patients with high HER2 expression. However, HER2-targeted ADC technology needs further optimization to improve its effect for the treatment of patients with low HER2 expression. We hypothesized that bispecific antibody–drug conjugate (bsADC) targeting HER2 and Sortilin-1 (SORT1) would overcome this limitation. SORT1 is a suitable target for pairing with HER2 to generate a bispecific antibody (BsAb) since the gene is co-expressed with HER2 in tumors and possesses rapid internalization. We developed a BsAb (bsSORT1×HER2) that exhibited strong binding and internalization activity on HER2-low-expression tumor cells and facilitated higher HER2 degradation. The bsSORT1×HER2 was further conjugated with DXd to generate a bsADC (bsSORT1×HER2-DXd) that showed strong cytotoxicity on HER2-low-expression tumor cells and antitumor efficacy in an MDA-MB-231 xenograft mice model. These results demonstrated that employment of a SORT1×HER2-targeted bsADC may be promising to improve the antitumor efficacy of HER2-targeted ADC for the treatment of tumors with low HER2 expression. [ABSTRACT FROM AUTHOR]

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As a class of nanomaterials with natural enzyme-like characteristics, nanozymes have shown their great potential in various applications. Reducible metal oxides featured with defect structures, and single-atom catalysts with isolated metal sites are regarded as two of the most promising nanozymes. However, the strategies to construct highly performed nanozymes by combining these advantages are rarely reported. Herein, we report the coordination-unsaturated single-atomic Cu species supported on sintered CeO2, which combines the advantages of defect engineering and single-atom catalysis, exhibiting a largely enhanced peroxidase (POD)-like activity. The high-temperature calcination induces the transformation of inert Cu1O4 species into coordination-unsaturated Cu1O3 sites. This novel Cu1O3 active sites with an unsaturated coordination work as a new type of defect sites to greatly activate the isolated Cu atoms and accelerate the dissociation of H2O2 to form hydroxyl radicals (·OH). The obtained nanozyme with a high POD-like activity possesses low cytotoxicity, showing potential applications for the tumor inhibition in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Osteosarcoma is an aggressive malignant tumor that primarily develops in children and adolescents. The conventional treatments for osteosarcoma often exert negative effects on normal cells, and chemotherapeutic drugs, such as platinum, can lead to multidrug resistance in tumor cells. Herein, this work reports a new bioinspired tumor‐targeting and enzyme‐activatable cell‐material interface system based on DDDEEK‐pY‐phenylboronic acid (SAP‐pY‐PBA) conjugates. Using this tandem‐activation system, this work selectively regulates the alkaline phosphatase (ALP) triggered anchoring and aggregation of SAP‐pY‐PBA conjugates on the cancer cell surface and the subsequent formation of the supramolecular hydrogel. This hydrogel layer can efficiently kill osteosarcoma cells by enriching calcium ions from tumor cells and forming a dense hydroxyapatite layer. Owing to the novel antitumor mechanism, this strategy neither hurts normal cells nor causes multidrug resistance in tumor cells, thereby showing an enhanced tumor treatment effect than the classical antitumor drug, doxorubicin (DOX). The outcome of this research demonstrates a new antitumor strategy based on a bioinspired enzyme‐responsive biointerface combining supramolecular hydrogels with biomineralization. [ABSTRACT FROM AUTHOR]

Cisplatin is the leading chemotherapy agent for advanced liver cancer. However, the resistance to cisplatin in liver cancer reduces its efficacy. A potential strategy to increase its effectiveness and reduce toxicity is to combine cisplatin with 1,3,8-trihydroxy-6-methylanthraquinone (emodin). In this study, we examined the effects of emodin combined with cisplatin on the invasion and migration of HepG2 cells and analyzed the role of emodin. The effects of cisplatin, emodin and their combination were assessed in HepG2 cells. Proliferation, invasion and migration of HepG2 cells were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), scar and Transwell assays. The gelatinase spectrum and an ELISA detected the expression of matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9). The expression of E-cadherin and vimentin was detected by immunofluorescence and Western blots. Emodin inhibited cell invasion and migration in HepG2 hepatoma cells, increased E-cadherin expression, decreased vimentin, MMP-2, and MMP-9 expression. The combination of emodin and cisplatin-induced a more significant effect in a dose-dependent manner. In this study, we found that emodin inhibited hepatocellular carcinoma (HCC) metastasis. Compared with either cisplatin or emodin alone, the combination of both showed a more significant synergistic effect. Emodin can enhance the sensitivity of HepG2 HCC cells to cisplatin by inhibiting epithelialmesenchymal transition, and thus, play a role in preventing recurrence and metastasis in HCC. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype with poor prognoses and limited therapeutic options. The TATA-box binding protein associated factor 1 (TAF1) is an essential protein involved in the transcriptional regulation of cancer development and progress. However, the therapeutic potential and underlying mechanism of targeting TAF1 in TNBC remain unknown. Here, using chemical probe BAY-299, we identify that TAF1 inhibition leads to the induction of endogenous retrovirus (ERVs) expression and double-stranded RNA (dsRNA) formation, resulting in the activation of interferon responses and cell growth suppression in a subset of TNBC, resembling anti-viral mimicry effect. This correlation between TAF1 and interferon signature was validated in three independent breast cancer patient datasets. Furthermore, we observe heterogeneous responses to TAF1 inhibition across a set of TNBC cell lines. By integrating transcriptome and proteome data, we demonstrate that high levels of proliferating cell nuclear antigen (PCNA) protein serve as a predictive biomarker associated with suppressive tumor immune responses in various cancers, which may limit the efficiency of TAF1 inhibition. • Identification of TAF1 as a novel pharmacological target for triple-negative breast cancer (TNBC). • Discovery of the negative correlation between TAF1 expression and tumor immunity in TNBC. • Detailed elucidation of the molecular mechanism underlying interferon activation upon TAF1 inhibition. • Identification of high PCNA level as a predictive biomarker for suppressive immunity limiting TAF1 inhibition efficacy. [ABSTRACT FROM AUTHOR]

Magnesium ions are essential elements to the human body, with a daily intake of about 350 mg for an adult. Recently, a meta-analysis reported that magnesium ion intake is related to a reduced risk of colorectal tumors. In addition, implantation of biodegradable magnesium pins after colorectal tumor resection could potentially inhibit the residual tumor cells. These impressive results implied that magnesium ions possess inhibitory properties against colorectal carcinoma. However, this hypothesis has yet to be confirmed by experimental results. In this work, different concentrations of magnesium ions were modulated to investigate their inhibitory effects on cell viability through cell cycle arrest, subsequently inducing apoptosis by activating the caspase-3 pathway. The animal experiments revealed that magnesium injection restricted tumor growth after 3 weeks of treatment compared to the control group. According to the immunohistochemistry and transmission electron microscopy results, the remarkable effect may be attributed to promoting the apoptotic rate of tumor cells. The evidence highlights the potential for the clinical use of magnesium implants to inhibit the growth of residual cells after colorectal tumor surgery. [ABSTRACT FROM AUTHOR]

Photothermal therapy directly acting on the nucleus is a potential anti-tumor treatment with higher killing efficiency. However, in practical applications, it is often difficult to achieve precise nuclear photothermal therapy because agents are difficult to accurately anchor to the nucleus. Therefore, it is urgent to develop a nanoheater that can accurately locate the nucleus. Here, we designed an amphiphilic arginine-rich dendritic peptide (RDP) with the sequence CRRK(RRCG(Fmoc))2, and prepared a nucleus-targeting nanoplatform RDP/I by encapsulating the photothermal agent IR780 in RDP for precise photothermal therapy of the tumor nucleus. The hydrophobic group Fmoc of the dendritic peptide provides strong hydrophobic force to firmly encapsulate IR780, which improves the solubility and stability of IR780. Moreover, the arginine-rich structure facilitates cellular uptake of RDP/I and endows it with the ability to quickly anchor to the nucleus. The nucleus-targeting nanoplatform RDP/I showed efficient nuclear enrichment ability and a significant tumor inhibition effect. [ABSTRACT FROM AUTHOR]

Centromere protein K (CENPK) is a newly identified malignancy-related gene that exhibits differential expression in various cancers and plays a crucial role in carcinogenesis. However, it remains uncertain whether CENPK is involved in clear cell renal cell carcinoma (ccRCC). This work aimed to unveil the expression, clinical significance, biological functions, and regulatory mechanisms of CENPK in ccRCC. Through analysis of RNA-seq data obtained from TCGA, a high expression pattern of CENPK was identified in ccRCC, which was found to be associated with pathologic stage, histologic grade, and clinical outcome. The enrichment of CENPK in ccRCC was further verified through the analysis of clinical samples. By conducting cellular functional experiments, we showed an inhibitory effect of CENPK knockdown on the malignant behavior of ccRCC cells. GSEA revealed a close relationship between CENPK and the Hippo–YAP1/TAZ signal cascade. The following experiments demonstrated that the activation of YAP1/TAZ was strongly inhibited by CENPK knockdown, and this change was accompanied by a decrease in the levels of CTGF and CYR61. Blockade of the MST1/2-LATS1/2 axis reversed the suppressive impact of CENPK knockdown on YAP1/TAZ. The tumor-promoting impact observed upon CENPK overexpression was diminished in YAP1 knockout cells. Notably, ccRCC cells with reduced CENPK expression exhibited a diminished capability to form tumors in nude mice. This report highlights the importance of CENPK in ccRCC and sheds new light on the underlying mechanism of this cancer type. Therefore, CENPK has the potential to serve as a viable candidate target for treating ccRCC. [Display omitted] • CENPK was overexpressed in ccRCC and had a diagnostic and prognostic value. • CENPK knockdown inhibited the malignant behavior of ccRCC cells. • CENPK suppressed the activation of YAP1/TAZ via the MST1/2-LATS1/2 axis. • CENPK enhanced ccRCC progression by the MST1/2-LATS1/2-YAP1/TAZ pathway. [ABSTRACT FROM AUTHOR]

Oxidative stress can attack precursor nucleotides, resulting in nucleic acid damage in cells. It remains unclear how 8-oxo-dGTP and 8-oxoGTP, oxidized forms of dGTP and GTP, respectively, could affect DNA or RNA oxidation levels and tumor development. To address this, we intravenously administered 8-oxo-dGTP and 8-oxoGTP to wild-type and MTH1 -knockout mice. 8-oxoGTP administration increased frequency of tumor incidence, which is more prominent in MTH1 -knockout mice. However, 8-oxo-dGTP treatment rather reduced tumor development regardless of the mouse genotype. The tumor suppressive effects of 8-oxo-dGTP were further confirmed using xenograft and C57/6J-ApcMin/Nju mouse models. Mechanistically, 8-oxo-dGTP increased the 8-oxo-dG contents in DNA and DNA strand breakage, induced cell cycle arrest in S phase and apoptosis mediated by AIF, eventually leading to reduced tumor incidence. These results suggest distinct roles of 8-oxo-dGTP and 8-oxoGTP in tumor development. [Display omitted] • 8-oxo-dGTP does not increase but rather prevents tumors in MTH1 -KO and WT mice. • 8-oxo-dGTP inhibits the growth of xenograft tumors and intestinal polypoid tumors. • 8-oxo-dGTP increases 8-oxo-dG in DNA strands and causes DNA damage. • 8-oxo-dGTP causes the S-phase arrest and induces apoptosis mediated by AIF. [ABSTRACT FROM AUTHOR]

KRAS mutations occur in a quarter of all human cancers. When activated in its GTP-bound form, RAS stimulates diverse cellular systems, such as cell division, differentiation, growth, and apoptosis through the activations of various signaling pathways, which include mitogen-activated protein kinase (MAPK), phosphoinositide 3 kinases (PI3K), and RAL-GEFs pathways. We found that GJ101 (65LYDVA69) binds directly to the KRAS mutant (G12V) and showed tumor-suppressive activity. In addition, the GJ101 peptide inhibited KRAS mutant as determined by a [α-32P] guanosine triphosphate (GTP) binding assay and suppressed pancreatic cell line in a cell proliferation assay. Herein, the complex structure of KRAS and GJ101 was clarified by X-ray crystallography. Isothermal titration calorimetry showed that GJ101 binds highly with KRAS mutant and the complex structure of KRAS G12V. GJ101 complex presented that the residue of Q61 directly interacted with L65 of GJ101. Overall, the results suggest GJ101 be considered a developmental starting point for KRAS G12V inhibitor. • The crystal structure of KRAS G12V. GJ101 complex was determined. • The residue of Q61 in KRAS G12V directly interacted with L65 of GJ101. • GJ101 suppressed RAS activation and function. • GJ101 can be as novel anti-cancer agent for PDAC. • The KRAS G12V was physically bound to GJ101 with an apparent K D value. [ABSTRACT FROM AUTHOR]

Saline environments are largely unexplored sources of actinomycetes with the potential to produce biologically active secondary metabolites. A total of 34 actinomycete isolates from water, sediments and mostly rhizosphere (82%) were collected from different sites at Howz Soltan Lake in Iran. Based on phylogenetic analysis, the isolates belonged to the genera Streptomyces, Nocardia and Saccharomonospora. Cytotoxic assay revealed extract from isolate act9 as the most potent (19.716±5.72 µg/ml) against the MDA-MB-231 human breast cancer cell. Also, 38% of the isolates showed antimicrobial activity against some of the test microorganisms. The ethyl-acetate extract of isolate act18 showed the strongest antibacterial effect against Staphylococcus aureus and MRSA, and was further analyzed by GC/MS. Ar-tumerone (26.41%) and butyl isodecyl phthalate (21.77 %) were the main constituents detected in the extract. This is the first time Ar-tumerone is being detected in a prokaryote. Isolate act18 showed a high 16S rRNA sequence similarity to that of Streptomyces youssoufiensis DSM 41920. In addition, a number of the isolates produced different enzymes including lipase, amylase, protease, gelatinase, urease and lecithinase. Some of the isolates belonging to the genera Streptomyces and Nocardia exhibited plant growth promoting activity such as increased seed germination, stem length and the number of Echium leaves during the 20 days. Findings from this study indicated the diversity and biosynthetic potential of actinomycetes from saline environment. [ABSTRACT FROM AUTHOR]

Polyoxometalates (POMs) have shown promising antitumor activities attributed to their virtue of incomparable structural versatility and interesting redox properties. However, the clinical application of POM drugs is limited by their poor stability and low anticancer specificity. To overcome these shortcomings, a multifunctional platform based on POMs (the tetrabutylammonium salts of [PW12O40]3−, [V10O28H3]3− and [Mo6O19]2−) and MIL-100 (Fe) was successfully developed for combined chemical and chemodynamic therapy, ultimately inducing cancer cell apoptosis. The prepared POMs@MIL-100 (Fe) composites showed great efficiency in killing MCF-7 and 4T1 cells while with a low toxicity to normal MCF-10A and C2C12 cells.

Objective·To investigate the anti-cancer effects of DNA nanoflowers (DF) loaded with horseradish peroxidase (HRP) and doxorubicin (DOX) on mice Lewis lung carcinoma (LLC) cells. Methods·The DF loaded with HRP (HRP-DF) was synthesized by rolling circle amplification (RCA) reaction and DOX was loaded to prepare DOX/HRP-DF, the physical properties of which were detected by scanning electron microscopy and laser particle sizer. In vitro drug release capacity of DOX/HRP-DF was tested with acid buffer solution. The safety of DOX/HRP-DF was evaluated by CCK-8 assay to detect the cytotoxicity of 16HBE cells treated with DOX/HRP-DF and free DOX at different time points. Under anoxic conditions, the oxygen production capacity of DOX/HRP-DF in LLC cells was detected by using the oxygen-sensitive probe, and the effects of different dosages of free DOX, DOX-DF and DOX/HRP-DF on the proliferation capacity of LLC cells were examined by CCK-8 assay. The effects of DOX/HRP-DF on the migration and invasion of LLC cells were detected by scratching assay and Transwell assay in the experimental group treated with different dosages of DOX/HRP-DF and the control group treated with Phosphate Buffered Saline (PBS). Results·DOX/HRP-DF were successfully prepared and observed as flower-like structures under scanning electron microscopy with uniform size. The average diameter and potential of DOX/HRP-DF were (415.90±9.32) nm and (-17.43±1.20) mV, respectively. DOX/HRP-DF had a DOX loading of (38.19±0.39)% with good pH-sensitive drug release properties. DOX/HRP-DF could significantly reduce the toxic effect of DOX on human normal cells. The results of Laser confocal microscopy showed that DOX/HRP-DF could effectively alleviate the hypoxic condition of LLC cells. CCK-8 assay results showed that the proliferation rate of LLC cells in the DOX/HRP-DF group was significantly lower in a dose-dependent manner, compared to the free DOX and DOX-DF groups (P<0.05). The results of scratching assay showed that the scratch healing rate of the DOX/HRP-DF group was lower than that of PBS group in a dose-dependent manner (P<0.05). Transwell experiments showed the number of LLC cells passing through Matrigel gel in the DOX/HRP-DF group was reduced in a dose-dependent manner, compared with the PBS group (P< 0.05). Conclusion·The successfully prepared DOX/HRP-DF could effectively deliver drugs, and alleviate hypoxia in the tumor microenvironment, and significantly inhibit the proliferation, migration and invasion ability of LLC cells, which is expected to provide new ideas for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract Nanoparticles, presenting catalytic activity to induce intracellular oxidative species, have been extensively explored for tumor treatment, but suffer daunting challenges in the limited intracellular H2O2 and thus suppressed therapeutic efficacy. Here in this study, a type of composite nanoparticles, consisting CaO2 core and Co-ferrocene shell, is designed and synthesized for combinational tumor treatment. The findings indicate that CaO2 core can be hydrolyzed to produce large amounts of H2O2 and calcium ions at the acidic tumor sites. Meanwhile, Co-ferrocene shell acts as an excellent Fenton catalyst, inducing considerable ROS generation following its reaction with H2O2. Excessive cellular oxidative stress triggers agitated calcium accumulation in addition to the calcium ions released from the particles. The combined effect of intracellular ROS and calcium overload causes significant tumor inhibition both in vitro and in vivo.

Triple-negative breast cancer (TNBC) is a highly aggressive subset of breast cancer with limited therapeutic options. However, its immune evasion mechanisms, characterized by the over-expression of the immune checkpoint molecules PD-L1 and CD47, can be targeted in order to facilitate cancer elimination by cells of innate and adaptive immunity. In this paper, we describe the design, preparation, and evaluation of three novel dual-targeting fusion proteins that were based on the structure frame of prototype IAB (innate and adaptive dependent bispecific fusion protein) and the "Orcutt-type IgG-scFv" molecular model. Three molecules with different spatial conformations were designed to improve antigen–antibody affinity by the addition of Ag–Ab binding sites from the variable region sequences of the anti-PD-L1 monoclonal antibody (mAb) atezolizumab and CV1, a high-affinity receptor of CD47. The results showed that the best-performing among the three proteins designed in this study was protein Pro3; its CV1 N-terminus and Fc domain C-terminus were not sterically hindered. Pro3 was better at boosting T cell proliferation and the engulfment of macrophages than the IAB prototype and, at the same time, retained a level of ADCC activity similar to that of IAB. Through improved design, the novel constructed dual-targeting immunomodulatory protein Pro3 was superior at activating the anti-tumor immune response and has thus shown potential for use in clinical applications. [ABSTRACT FROM AUTHOR]

Velvet antleris a non-ossified regeneration organ of male deer covered by velvet skin. The regeneration process of velvet antler is regulated by many bioactive substances and has a similar growth process to tumor development, but the growth of tumor cells is out of control and malignant, while velvet antler is a controllable development process. In some studies, the inhibitory effect of velvet antler extract on malignant tumors has made some progress. In this paper, the biological basis of velvet antler regeneration and the bioactive components of velvet antler extract were described, and the effects and research progress of velvet antler extract on prostate cancer, breast cancer, glioblastoma and colon cancer were summarized, in order to provide further reference for the role of velvet antler extract in cancer treatment. [ABSTRACT FROM AUTHOR]

Cancer is the second leading cause of death worldwide. Cervical cancer, for instance, is considered a major scourge in low-income countries. Its development is mostly associated with the human papillomavirus persistent infection and despite the availability of preventive vaccines, they are only widely administered in more developed countries, thus leaving a large percentage of unvaccinated women highly susceptible to this type of cancer. Current treatments are based on invasive techniques, being far from effective. Therefore, the search for novel, advanced and personalized therapeutic approaches is imperative. Flavonoids belong to a group of natural polyphenolic compounds, well recognized for their great anticancer capacity, thus promising to be incorporated in cancer therapy protocols. However, their use is limited due to their low solubility, stability and bioavailability. To surpass these limitations, the encapsulation of flavonoids into delivery systems emerged as a valuable strategy to improve their stability and bioavailability. In this context, the aim of this review is to present the most reliable flavonoids-based delivery systems developed for anticancer therapies and the progress accomplished, with a special focus on cervical cancer therapy. The gathered information revealed the high therapeutic potential of flavonoids and highlights the relevance of delivery systems application, allowing a better understanding for future studies on effective cancer therapy. [ABSTRACT FROM AUTHOR]

In this study, we demonstrate that Raman microscopy combined with computational analysis is a useful approach to discriminating accurately between brain tumor bio-specimens and to identifying structural changes in glioblastoma (GBM) bio-signatures after nordihydroguaiaretic acid (NDGA) administration. NDGA phenolic lignan was selected as a potential therapeutic agent because of its reported beneficial effects in alleviating and inhibiting the formation of multi-organ malignant tumors. The current analysis of NDGA's impact on GBM human cells demonstrates a reduction in the quantity of altered protein content and of reactive oxygen species (ROS)-damaged phenylalanine; results that correlate with the ROS scavenger and anti-oxidant properties of NDGA. A novel outcome presented here is the use of phenylalanine as a biomarker for differentiating between samples and assessing drug efficacy. Treatment with a low NDGA dose shows a decline in abnormal lipid-protein metabolism, which is inferred by the formation of lipid droplets and a decrease in altered protein content. A very high dose results in cell structural and membrane damage that favors transformed protein overexpression. The information gained through this work is of substantial value for understanding NDGA's beneficial as well as detrimental bio-effects as a potential therapeutic drug for brain cancer. [ABSTRACT FROM AUTHOR]

CD47 is a widely expressed cell-surface protein that regulates phagocytosis mediated by cells of the innate immune system, such as macrophages and dendritic cells. CD47 serves as the ligand for a receptor on these innate immune cells, signal regulatory protein (SIRP)-α, which in turn inhibits phagocytosis. Several targeted CD47 therapeutic antibodies have been investigated clinically; however, how to improve its therapeutic efficacy remains unclear. Herein, we developed a CD47 blocking antibody, named IBI188, that could specifically block the CD47-SIRP-α axis, which transduces the "don't eat me" signal to macrophages. In vitro phagocytosis assays demonstrated the pro-phagocytosis ability of IBI188. Furthermore, several in vivo models were chosen to evaluate the anti-tumor efficacy of IBI188. IBI188 treatment upregulated cell movement- and inflammation-related genes in macrophages. Synergism was observed when combined with an anti-CD20 therapeutic antibody, whose function depends on antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP). CD47 expression was evaluated following azacytidine (AZA) treatment, a standard-of-care for patients with multiple myeloma; enhanced anti-tumor efficacy was observed in the combination group in AML xenograft models. Notably, IBI188 treatment increased vascular endothelial growth factor-A (VEGF-A) levels in a solid tumor model, and combined treatment with an anti-VEGF-A antibody and IBI188 resulted in an enhanced anti-tumor effect. These data indicate that IBI188 is a therapeutic anti-CD47 antibody with anti-tumor potency, which can be enhanced when used in combination with standard-of-care drugs for cancer treatment. [ABSTRACT FROM AUTHOR]

Hydroxyapatite nanoparticles (HANPs) have been increasingly regarded and reported due to their potential anti-tumor ability. Previously, we found that the rod-like HANPs had good application potential for cutaneous melanoma (CMM). To satisfy the actual requirements in repairing post-operative skin defects and inhibiting CMM recurrence after tumorectomy, we constructed a novel chitosan/alginate (CS/Alg) hydrogel containing the aforementioned HANPs. The in vitro cell experiments confirmed that activated mitochondrial-dependent apoptosis was tightly related to the anti-tumor ability of HANPs. Specifically, we further discovered several target proteins might be involved in abnormal activating Wnt, proteoglycans in cancer, oxidative phosphorylation and p53 signaling pathways. The in vivo animal experiments demonstrated that the HANPs-loaded CS/Alg hydrogel (CS/Alg/HANPs) had a similar effect on inhibiting tumor growth as HANPs, and CS/Alg hydrogel as well as phosphate buffered saline (PBS) group (control) not showed any effect, proving the key role of HANPs. The immunohistochemical staining demonstrated a tumor inhibition via the mitochondria-mediated apoptosis pathway, consistent with the in vitro evaluation. Moreover, CS/Alg/HANPs exhibited no additional biosafety risk to the functions of major organs. Overall, this CS/Alg/HANPs hydrogel has substantial application potential for treating CMM. [ABSTRACT FROM AUTHOR]

Nanoparticles, presenting catalytic activity to induce intracellular oxidative species, have been extensively explored for tumor treatment, but suffer daunting challenges in the limited intracellular H2O2 and thus suppressed therapeutic efficacy. Here in this study, a type of composite nanoparticles, consisting CaO2 core and Co-ferrocene shell, is designed and synthesized for combinational tumor treatment. The findings indicate that CaO2 core can be hydrolyzed to produce large amounts of H2O2 and calcium ions at the acidic tumor sites. Meanwhile, Co-ferrocene shell acts as an excellent Fenton catalyst, inducing considerable ROS generation following its reaction with H2O2. Excessive cellular oxidative stress triggers agitated calcium accumulation in addition to the calcium ions released from the particles. The combined effect of intracellular ROS and calcium overload causes significant tumor inhibition both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Smad4, a critical mediator of TGF-β signaling, plays a pivotal role in regulating various cellular functions, including immune responses. In this study, we investigated the impact of Smad4 knockout specifically in macrophages on anti-tumor immunity, focusing on lung metastasis of B16 melanoma cells. Using a mouse model with Smad4 knockout in macrophages established via Lyz2-cre mice and Smad4 flox/flox mice, we demonstrated a significant inhibition of B16 metastasis in the lungs. Interestingly, the inhibition of tumor growth was found to be independent of adaptive immunity, as no significant changes were observed in the numbers or activities of T cells, B cells, or NK cells. Instead, Smad4 knockout led to the emergence of an MCHIIlow CD206high subset of lung interstitial macrophages, characterized by enhanced phagocytosis function. Our findings highlight the crucial role of Smad4 in modulating the innate immune response against tumors and provide insights into potential therapeutic strategies targeting lung interstitial macrophages to enhance anti-tumor immunity. • Smad4 knockout in macrophages blocks B16 melanoma lung metastasis, emphasizing its role in tumor spread. • Tumor inhibition via Smad4 knockout independent of adaptive immunity highlights unique metastasis suppression. • Smad4 deficiency alters lung macrophage phenotype, enhancing phagocytic activity, informing cancer therapy strategies. [ABSTRACT FROM AUTHOR]

Song Kwon,1,* Kwai Han Yoo,2,* Sun Jin Sym,2 Dongwoo Khang1,3,41Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, South Korea; 2Department of Internal Medicine, Division of Hematology, School of Medicine, Gachon University Gil Medical Center, Incheon, 21565, South Korea; 3Department of Gachon Advanced Institute for Health Science & Technology (Gaihst), Gachon University, Incheon 21999, South Korea; 4Department of Physiology, School of Medicine, Gachon University, Incheon 21999, South Korea*These authors contributed equally to this workAbstract: Mesenchymal stem cells (MSCs) intrinsically possess unique features that not only help in their migration towards the tumor-rich environment but they also secrete versatile types of secretomes to induce nerve regeneration and analgesic effects at inflammatory sites. As a matter of course, engineering MSCs to enhance their intrinsic abilities is growing in interest in the oncology and regenerative field. However, the concern of possible tumorigenesis of genetically modified MSCs prompted the development of non-viral transfected MSCs armed with nanotechnology for more effective cancer and regenerative treatment. Despite the fact that a large number of successful studies have expanded our current knowledge in tumor-specific targeting, targeting damaged brain site remains enigmatic due to the presence of a blood–brain barrier (BBB). A BBB is a barrier that separates blood from brain, but MSCs with intrinsic features of transmigration across the BBB can efficiently deliver desired drugs to target sites. Importantly, MSCs, when mediated by nanoparticles, can further enhance tumor tropism and can regenerate the damaged neurons in the central nervous system through the promotion of axon growth. This review highlights the homing and nerve regenerative abilities of MSCs in order to provide a better understanding of potential cell therapeutic applications of non-genetically engineered MSCs with the aid of nanotechnology.Keywords: glioblastoma multiforme, tumor inhibition, mesenchymal stem cell, nanocarrier, nerve regeneration, anti-inflammation

Photothermal‐chemotherapeutic nanoparticles (NPs) are attracting increasing attention and becoming more widely used for cancer therapy in the clinic due to their noninvasiveness, notable tissue penetration abilities, and low systemic adverse effects. However, functional ligands are conventionally modified onto photothermal NPs to well stabilize the inorganic particles suffering from complex chemical modifications, low productivity, and batch‐to‐batch inconsistencies, and thus significantly restricting their clinical applications. Herein, flash nanoprecipitation (FNP) is taken advantage of to afford rapid and uniform mixing for generating local supersaturated CuS clusters for small and highly stable CuS NPs effectively stabilized by polyacrylic acid through a continuous strategy. It greatly reduces the complexity for CuS NPs synthesis and functionalization in a facile intensified mixing process. These as‐synthesized particles are high‐drug loading, scalable, and most importantly, it is easy to control their sizes and charges through external conditions. Toxicity and tumor inhibition experiments confirm the high cell toxicity and good suppression of tumor growth under near‐infrared irradiation indicating a promising prospect of FNP in the large‐scale and continuous yielding of highly stable and high‐performing photothermal‐chemotherapeutic NPs for cancer therapy. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is prevalent worldwide and has a high mortality rate. Even if mesenchymal stem cells (MSCs) are suggested as cancer treatment, the studies of their effects on NSCLC cells contradict each other, mainly due to utilization of two-dimensional (2D) culture system. Three-dimensional (3D) culture systems resemble tissue organization in vivo. Here we comprehensively explore the inhibitory effects of MSCs on NSCLC cells in a 3D culture system. We confirmed that the inhibitory effects of 3D-cultured MSCs (3D-MSCs) on the proliferation and migration of NSCLC cells are greater than that of the 2D-cultured MSCs. The expression of IL-24 in 3D-MSCs is higher than 2D-MSCs, which is the key factor to enhance the anti-tumor effect of MSCs. In these cells, IL-24 affects p38 MAPK and CXCR4/AKT pathways. Overall, this study provides the support for use of MSCs in tumor therapy. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a highly aggressive subset of breast cancer with limited therapeutic options. However, its immune evasion mechanisms, characterized by the over-expression of the immune checkpoint molecules PD-L1 and CD47, can be targeted in order to facilitate cancer elimination by cells of innate and adaptive immunity. In this paper, we describe the design, preparation, and evaluation of three novel dual-targeting fusion proteins that were based on the structure frame of prototype IAB (innate and adaptive dependent bispecific fusion protein) and the “Orcutt-type IgG-scFv” molecular model. Three molecules with different spatial conformations were designed to improve antigen–antibody affinity by the addition of Ag–Ab binding sites from the variable region sequences of the anti-PD-L1 monoclonal antibody (mAb) atezolizumab and CV1, a high-affinity receptor of CD47. The results showed that the best-performing among the three proteins designed in this study was protein Pro3; its CV1 N-terminus and Fc domain C-terminus were not sterically hindered. Pro3 was better at boosting T cell proliferation and the engulfment of macrophages than the IAB prototype and, at the same time, retained a level of ADCC activity similar to that of IAB. Through improved design, the novel constructed dual-targeting immunomodulatory protein Pro3 was superior at activating the anti-tumor immune response and has thus shown potential for use in clinical applications.

Success of targeted cancer treatment modalities has generated an ambience of plausible cure for cancer. However, cancer remains to be the major cause of mortality across the globe. The emergence of chemoresistance, relapse after treatment and associated adverse effects has posed challenges to the present therapeutic regimes. Thus, investigating new therapeutic agents of natural origin and delineating the underlying mechanism of action is necessary. Since ages and still in continuum, the phytochemicals have been the prime source of identifying bioactive agents against cancer. They have been exploited for isolating targeted specific compounds to modulate the key regulating signaling pathways of cancer pathogenesis and progression. Capsaicin (alkaloid compound in chilli), catechin, epicatechin, epigallocatechin and epigallocatechin-3-gallate (phytochemicals in green tea), lutein (carotenoid found in yellow fruits), Garcinol (phenolic compound present in kokum tree) and many other naturally available compounds are also very valuable to develop the drugs to treat the cancer. An alternate repository of similar chemical diversity exists in the form of endophytic fungi inhabiting the medicinal plants. There is a high diversity of plant associated endophytic fungi in nature which are potent producers of anti-cancer compounds and offers even stronger hope for the discovery of an efficient anti-cancer drug. These fungi provide various bioactive molecules, such as terpenoids, flavonoids, alkaloids, phenolic compounds, quinines, steroids etc. exhibiting anti-cancerous property. The review discusses the relevance of phytochemicals in chemoprevention and as modulators of miRNA. The perspective advocates the imperative role of anti-cancerous secondary metabolites containing repository of endophytic fungi, as an alternative route of drug discovery. [ABSTRACT FROM AUTHOR]

PUMA (p53-upregulated modulator of apoptosis) is localized in mitochondria and a direct target in p53-mediated apoptosis. p53 elicits mitochondrial apoptosis via transcription-dependent and independent mechanisms. p53 is known to induce apoptosis via the transcriptional induction of PUMA, which encodes proapoptotic BH3-only members of the Bcl-2 protein family. However, the transcription-independent mechanisms of human PUMA remain poorly defined. For example, it is not known whether PUMA interacts directly with the DNA binding domain (DBD: residues 92–293) of p53 in vitro. Here, the structure of the complex between the DBD of p53 and PUMA peptide was elucidated by X-ray crystallography. Isothermal titration calorimetry showed that PUMA peptide binds strongly with p53 DBD, and the crystal structure of p53-PUMA peptide complex revealed it contains four molecules of p53 DBD and one PUMA peptide per asymmetric unit in space group P 1. PUMA peptide bound to the N-terminal residues of p53 DBD. A cell proliferation assay demonstrated PUMA peptide inhibited the growth of a lung cancer cell line. These results contribute to understanding of the mechanism responsible for p53-mediated apoptosis. • The PUMA gene is a transcriptional target of p53. • The first crystal structure of p53 DBD and PUMA complex was determined. • PUMA peptide inhibited the growth of a lung cancer cell line. • These findings provide further insight of potential drug targets for cancer therapy. • The p53 DBD was physically bound to PUMA peptide with an apparent K D value. [ABSTRACT FROM AUTHOR]

Hongfeng Wu,1 Zhongtao Li,2 Jiaoqing Tang,2 Xiao Yang,1 Yong Zhou,3 Bo Guo,4 Lin Wang,2 Xiangdong Zhu,1 Chongqi Tu,3 Xingdong Zhang1 1National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China; 2Department of Dermatology, West China Hospital of Sichuan University, Chengdu 610041, China; 3Department of Orthopaedics, West China Hospital of Sichuan University, Chengdu 610041, China; 4Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China Background: Treatment for melanoma is a challenging clinical problem, and some new strategies are worth exploring.Purpose: The objective of this study was to investigate the in vitro and in vivo anti-melanoma effects of hydroxyapatite nanoparticles (HANPs) and discuss the involved material factors.Materials and methods: Five types of HANPs, ie, HA-A, HA-B, HA-C, HA-D, and HA-E, were prepared by wet chemical method combining with polymer template and appropriate post-treatments. The in vitro effects of the as-prepared five HANPs on inhibiting the viability of A375 melanoma cells and inducing the apoptosis of the cells were evaluated by Cell Counting Kit-8 analysis, cell nucleus morphology observation, flow cytometer, and PCR analysis. The in vivo anti-melanoma effects of HANPs were studied in the tumor model of nude mice.Results: The five HANPs had different physicochemical properties, including morphology, size, specific surface area (SSA), crystallinity, and so on. By the in vitro cell study, it was found that the material factors played important roles in the anti-melanoma effect of HANPs. Among the as-prepared five HANPs, HA-A with granular shape, smaller size, higher SSA, and lower crystallinity exhibited best effect on inhibiting the viability of A375 cells. At the concentration of 200 µg/mL, HA-A resulted in the lowest cell viability (34.90%) at day 3. All the HANPs could induce the apoptosis of A375 cells, and the relatively higher apoptosis rates of the cells were found in HA-A (20.10%) and HA-B (19.41%) at day 3. However, all the HANPs showed no inhibitory effect on the viability of the normal human epidermal fibroblasts. The preliminary in vivo evaluation showed that both HA-A and HA-C could delay the formation and growth speed of melanoma tissue significantly. Likely, HA-A exhibited better effect on inhibiting the growth of melanoma tissue than HA-C. The inhibition rate of HA-A for tumor tissue growth reached 49.1% at day 23.Conclusion: The current study confirmed the anti-melanoma effect of HANPs and provided a new idea for the clinical treatment of melanoma. Keywords: hydroxyapatite, nanoparticles, melanoma cells, fibroblasts, viability, apoptosis, tumor, suppression

Abstract Background Agarose encapsulated murine renal adenocarcinoma cells (RENCA macrobeads) are currently being investigated in clinical trials as a treatment for therapy-resistant metastatic colorectal cancer. We have previously demonstrated the capacity of RENCA macrobeads to produce diffusible substances that markedly inhibit the proliferation of epithelial-derived tumor cells outside the macrobead environment. This study examined the molecular mechanisms underlying the observed inhibition in targeted tumor cells exposed to RENCA macrobeads. Methods We evaluated changes in transcription factor responses, participating intracellular signaling pathways and the involvement of specific cellular receptors in targeted tumor cells exposed to RENCA macrobeads. Results Factors secreted by RENCA macrobeads significantly up-regulated the activity of the MEF2 transcription factor as well as altered the transcription of MEF2b and MEF2d isoforms in targeted tumor cells. Suppression of individual or multiple MEF2 isoforms in target tumor cells markedly reduced the growth inhibitory effects of RENCA macrobeads. Furthermore, these effects were linked to the activation of the EGF receptor as attenuation of EGFR resulted in a substantial reduction of the cancer cell growth-inhibitory effect. Conclusions Since interruption of the EGFR signaling cascade did not eliminate RENCA macrobead-induced growth control, our data suggests that RENCA macrobeads exert their full growth inhibitory effects through the simultaneous activation of multiple signaling pathways. In contrast to a precision medicine approach targeting single molecular abnormalities, the RENCA macrobead functions as a biological-systems therapy to re-establish regulation in a highly dysfunctional and dysregulated cancer system.

There is a pressing need for a ubiquitously expressed antigen or receptor on the tumor surface for successful mitigation of the deleterious side effects of chemotherapy. Phosphatidylserine (PS), normally constrained to the intracellular surface, is exposed on the external surface of tumors and most tumorigenic cell lines. Here we report that a novel PS-targeting liposome, phosphatidylcholine-stearylamine (PC-SA), induced apoptosis and showed potent anticancer effects as a single agent against a majority of cancer cell lines. We experimentally proved that this was due to a strong affinity for and direct interaction of these liposomes with PS. Complexation of the chemotherapeutic drugs doxorubicin and camptothecin in these vesicles demonstrated a manyfold enhancement in the efficacies of the drugs both in vitro and across three advanced tumor models without any signs of toxicity. Both free and drug-loaded liposomes were maximally confined to the tumor site with low tissue concentration. These data indicate that PC-SA is a unique and promising liposome that, alone and as a combination therapy, has anticancer potential across a wide range of cancer types.

Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4's core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4's substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds' cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4-expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability. [ABSTRACT FROM AUTHOR]

Abstract Targeted drug delivery systems (TDDSs) provide a promising approach to overcome the side effect of traditional chemotherapy by specific tumor targeting and drug release. Hyaluronan (HA), as a selective CD44 targeting group, has been widely used in TDDSs for chemotherapy. However, different molecular weight HAs would demonstrate different binding ability to CD44, which may result in different therapeutic effects. Herein, a silica/hydroxyapatite (MSNs/HAP) hybrid carrier loaded with anticancer drug doxorubicin (DOX) (DOX@MSNs/HAP) is fabricated. HA and oligo HA (oHA) are coated onto the nanoparticles (HA‐DOX@MSNs/HAP, oHA‐DOX@MSNs/HAP), respectively, to investigate their performance in tumor targeting ability. oHA‐DOX@MSNs/HAP shows much higher efficiency cellular uptake and drug release in tumor regions due to more effective CD44 targeting of oHA. Thus, the anticancer effect of oHA‐DOX@MSNs/HAP is significantly enhanced compared to HA‐DOX@MSNs/HAP, as demonstrated in a tumor‐bearing mouse model. This study may enable the rational design of nanodrug systems for future tumor‐targeted chemotherapy.

Pea-like nanocabins (HA@APT§DOX) were designed for deep tumor inhibition. The AS1411 aptamer (APT) constituted "core shelf" which guaranteed DOX "beans" could be embedded, while the outer HA acted as "pea shell" coating. During the circulation (primary orbit), HA@APT§DOX could autonomously cruise until leak through tumor vasculature. Upon tumor superficial site, the "pea shell" could be degraded by highly expressed hyaluronic acid enzymes (HAase) and peel-off, resulting in orbit changing of released APT§DOX to reach the deep tumor tissue. Furthermore, APT§DOX could be specifically uptaken into A549 tumor cells (secondary orbit). Finally, DOX was released under the acidic environment of lysosome, and delivered into nuclear (targeting orbit) to achieve drug pushing for deep tumor inhibition. More importantly, the in vivo imaging and anti-tumor effects evaluations showed that these nanocabins could effectively enhance drugs accumulation in tumor sites and inhibit tumor growth, with reduced systemic toxicity in 4T1 tumor-bearing mice. Pea-like nanocabins (HA@APT§DOX) were designed for deep tumor inhibition. The APT constituted "core shelf" which guaranteed DOX "beans" could be embedded, while the outer HA acted as "pea shell" coating. During the circulation, HA@APT§DOX could autonomously cruise until leak through tumor vasculature. Upon tumor superficial site, the "pea shell" could be degraded by highly expressed HAase and peel-off, resulting in orbit changing of APT§DOX to reach the deep tumor tissue. Furthermore, APT§DOX could be specifically identified and uptaken into A549 tumor cells, followed by the drug released under the acidic environment of lysosome, and delivered into nuclear for tumor therapy. Unlabelled Image [ABSTRACT FROM AUTHOR]

[Display omitted] • CuMPN has been constructed via a plasma immersion ion beam system. • CuMPN has excellent POD-like activity. • CuMPN can produce a large number of stable toxic hydroxyl radicals. • CuMPN exhibited excellent cytostatic rates in 4T1 and GL261 tumor cells. Producing reactive oxygen species within tumors is one of the main pathways inducing apoptosis or necrosis of malignant tumor cells. However, the active sites of MoS 2 nanozyme are mainly the S sites and defects at the edge, while the S sites on the basal plane are inactive, so the inhibitory effect of the MoS 2 nanozyme on tumor cells is limited. Herein, it is reported the Cu-doped pegylated MoS 2 nanozymes (Cu@MoS 2 -PEG, denoted CuMPN) were constructed via plasma immersion ion beam system (PIIB). Introducing Cu dopant, not only does it increase the electron density of the CuMPN surface, but also it has a high dispersibility in liquids, which makes it possible to effectively start the in-situ Fenton reaction, which produces a lot of harmful hydroxyl radicals (•OH) specifically in the tumor microenvironment (TME). The in vitro studies had manifested that the designed Cu 0.86 MPN nanozymes have efficient inhibitory effects on mouse breast cancer cells (4T1 cells) and glioma cells (GL261 cells), meanwhile exhibiting good biosafety against mouse fibroblasts (L929 cells). The use of plasma immersed ion beam systems opens a new path for the development of high efficiency and biosecurity nano-catalytic drugs. [ABSTRACT FROM AUTHOR]

• CuS nanosheet is a highly efficient ultrasound-controllable catalytic material. • Ultrasound-activated CO and ROS can trigger immunogenic cell death. • Oxygen generation relieves tumor hypoxia and reverses immunosuppression. Ultrasound-activated tumor catalytic therapy has great potential in clinical cancer treatment. However, the hypoxic and immunosuppressive tumor microenvironment impairs the efficacy of solid tumor treatment, leading to a high recurrence rate of metastatic cancer. Thus, reversing the tumor microenvironment remains a formidable challenge. To circumvent these critical issues, we employ ultrasound-activable carbon monoxide (CO) gas therapy and reactive oxygen species (ROS) production to trigger immunogenic cell death (ICD) and alleviate tumor hypoxia, achieving a combination of tumor therapy and reversal of immunosuppression to overcome the limitations of monotherapy and control tumor metastasis and recurrence. In brief, we first use copper sulfide (CuS) nanosheet as a highly efficient ultrasound-controllable catalytic nanomaterial, which can catalyze carbon dioxide, water, and oxygen to produce CO, oxygen, and ROS. Moreover, as a Fenton-like catalyst, it can catalyze hydrogen peroxide at tumor sites to generate ROS. The generated CO can attack mitochondria to accelerate their metabolism and produce more ROS, thus inducing ICD. In addition, the generation of oxygen can not only serve as the source of ROS, but it can also relieve tumor hypoxia and normalize the tumor immunosuppressive microenvironment. This results in the maturation of dendritic cells and the enhancement of T-lymphocyte recruitment and infiltration, further stimulating the antitumor immune response, mediating the regression of primary and distal tumors, and inhibiting lung metastasis. This in situ sono-activable catalytic therapy strategy minimizes the toxicity of CO and ROS leakage and provides a novel approach for designing new ICD inducers and improving therapeutic effects. [ABSTRACT FROM AUTHOR]