Intelligent gold nanocluster for effective treatment of malignant tumor via tumor-specific photothermal-chemodynamic therapy with AIE guidance.

Precise and efficient therapy of malignant tumors is always a challenge. Herein, gold nanoclusters co-modified by aggregation-induced-emission (AIE) molecules, copper ion chelator (acylthiourea) and tumor-targeting agent (folic acid) were fabricated to perform AIE-guided and tumor-specific synergistic therapy with great spatio-temporal controllability for the targeted elimination and metastasis inhibition of malignant tumors. During therapy, the functional gold nanoclusters (AuNTF) would rapidly accumulate in the tumor tissue due to the enhanced permeability and retention effect as well as folic acid-mediated tumor targeting, which was followed by endocytosis by tumor cells. After that, the overexpressed copper ions in the tumor cells would trigger the aggregation of these intracellular AuNTF via a chelation process that not only generated the photothermal agent in situ to perform the tumor-specific photothermal therapy damaging the primary tumor, but also led to the copper deficiency of tumor cells to inhibit its metastasis. Moreover, the copper ions were reduced to cuprous ions along with the chelation, which further catalysed the excess H2O2 in the tumor cells to produce cytotoxic reactive oxygen species, resulting in additional chemodynamic therapy for enhanced antitumor efficiency. The aggregation of AuNTF also activated the AIE molecules to present fluorescence, which not only imaged the therapeutic area for real-time monitoring of this tumor-specific synergistic therapy, but also allowed us to perform near-infrared radiation at the correct time point and location to achieve optimal photothermal therapy. Both in vitro and in vivo results revealed the strong tumor elimination, effective metastasis inhibition and high survival rate of tumor-bearing mice after treatment using the AuNTF nanoclusters, indicating that this AIE-guided and tumor-specific synergistic strategy could offer a promising approach for tumor therapy.

Intelligent nanoreactor coupling tumor microenvironment manipulation and H2O2-dependent photothermal-chemodynamic therapy for accurate treatment of primary and metastatic tumors.

Tumor microenvironment (TME), as the "soil" of tumor growth and metastasis, exhibits significant differences from normal physiological conditions. However, how to manipulate the distinctions to achieve the accurate therapy of primary and metastatic tumors is still a challenge. Herein, an innovative nanoreactor (AH@MBTF) is developed to utilize the apparent differences (copper concentration and H2O2 level) between tumor cells and normal cells to eliminate primary tumor based on H2O2-dependent photothermal-chemodynamic therapy and suppress metastatic tumor through copper complexation. This nanoreactor is constructed using functionalized MSN incorporating benzoyl thiourea (BTU), triphenylphosphine (TPP), and folic acid (FA), while being co-loaded with horseradish peroxidase (HRP) and its substrate ABTS. During therapy, the BTU moieties on AH@MBTF could capture excessive copper (highly correlated with tumor metastasis), presenting exceptional anti-metastasis activity. Simultaneously, the complexation between BTU and copper triggers the formation of cuprous ions, which further react with H2O2 to generate cytotoxic hydroxyl radical (•OH), inhibiting tumor growth via chemodynamic therapy. Additionally, the stepwise targeting of FA and TPP guides AH@MBTF to accurately accumulate in tumor mitochondria, containing abnormally high levels of H2O2. As a catalyst, HRP mediates the oxidation reaction between ABTS and H2O2 to yield activated ABTS•+. Upon 808 nm laser irradiation, the activated ABTS•+ performs tumor-specific photothermal therapy, achieving the ablation of primary tumor by raising the tissue temperature. Collectively, this intelligent nanoreactor possesses profound potential in inhibiting tumor progression and metastasis.

Targeting Trop2 by Bruceine D suppresses breast cancer metastasis by blocking Trop2/ß-catenin positive feedback loop.

INTRODUCTION: Tumor-associated calcium signal transducer 2 (Trop2) has been used as a transport gate for cytotoxic agents into cells in antibody-drug conjugate designs because of its expression in a wide range of solid tumors. However, the specific role of Trop2 itself in breast cancer progression remains unclear and small molecules targeting Trop2 have not yet been reported. OBJECTIVES: To screen small molecules targeting Trop2, and to reveal its pharmacological effects and the molecular mechanisms of action. METHODS: Small molecule targeting Trop2 was identified by cell membrane chromatography, and validated by cellular thermal shift assay and point mutation analyses. We investigated the pharmacological effects of Trop2 inhibitor using RNA-seq, human foreskin fibroblast (HFF)-derived extracellular matrix (ECM), Matrigel drop invasion assays, colony-forming assay, xenograft tumor model, 4T1 orthotopic metastasis model and 4T1 experimental metastasis model. The molecular mechanism was determined using immunoprecipitation, mass spectrometry, immunofluorescence, immunohistochemistry and Western blotting. RESULTS: Here we identified Bruceine D (BD) as the inhibitor of Trop2, and demonstrated anti-metastasis effects of BD in breast cancer. Notably, Lys307 and Glu310 residues of Trop2 acted as critical sites for BD binding. Mechanistically, BD suppressed Trop2-induced cancer metastasis by blocking the formation of Trop2/ß-catenin positive loop, in which the Trop2/ß-catenin complex prevented ß-catenin from being degraded via the ubiquitin-proteosome pathway. Destabilized ß-catenin caused by BD reduced nucleus translocation, leading to the reduction of transcription of Trop2, the reversal of epithelial-mesenchymal transition (EMT) process, and the inhibition of ECM remodeling, further inhibiting cancer metastasis. Additionally, the inhibitory effects of BD on lung metastatic colonization and the beneficial effects of BD on prolongation of survival were validated in 4T1 experimental metastasis model. CONCLUSIONS: These results support the tumor-promoting role of Trop2 in breast cancer by stabilizing ß-catenin in Trop2/ß-catenin positive loop, and suggest Bruceine D as a promising candidate for Trop2 inhibition.

Dauricine attenuates Oct4/sonic hedgehog co-activated stemness and induces reactive oxygen species-mediated mitochondrial apoptosis via AKT/ß-catenin signaling in human neuroblastoma and glioblastoma stem-like cells.

Neuroblastoma and glioblastoma are primary malignant tumors of the nervous system, with frequent relapse and limited clinical therapeutic drugs. The failure of their treatment is due to the tumor cells exhibiting cancer stem-like cells (CSLCs) properties. Octamer binding transcription factor 4 (Oct4) is involved in mediating CSLCs, our previous work found that Oct4-driven reprogramming of astrocytes into induced neural stem cells was potentiated with continuous sonic hedgehog (Shh) stimulation. In this study, we aimed to study the importance of Oct4 and Shh combination in the stemness properties induction of neuroblastoma and glioblastoma cells, and evaluate the anti-stemness effect of dauricine (DAU), a natural product of bis-benzylisoquinoline alkaloid. The effect of Oct4 and Shh co-activation on cancer stemness was evaluated by tumor spheres formation model and flow cytometry analysis. Then the effects of DAU on SH-SY5Y and T98-G cells were assessed by the MTT, colony formation, and tumor spheres formation model. DAU acts on Oct4 were verified using the Western blotting, MTT, and so on. Mechanistic studies were explored by siRNA transfection assay, Western blotting, and flow cytometry analysis. We identified that Shh effectively improved Oct4-mediated generation of stemness in SH-SY5Y and T98-G cells, and Oct4 and Shh co-activation promoted cell growth, the resistance of apoptosis. In addition, DAU, a natural product, was found to be able to attenuate Oct4/Shh co-activated stemness and induce cell cycle arrest and apoptosis via blocking AKT/ß-catenin signaling in neuroblastoma and glioblastoma, which contributed to the neuroblastoma and glioblastoma cells growth inhibition by DAU. In summary, our results indicated that the treatment of DAU may be served as a potential therapeutic method in neuroblastoma and glioblastoma.

Cantharidin induces apoptosis of human triple negative breast cancer cells through mir-607-mediated downregulation of EGFR.

BACKGROUND: Triple negative breast cancer (TNBC) is a major subtype of breast cancer, with limited therapeutic drugs in clinical. Epidermal growth factor receptor (EGFR) is reported to be overexpressed in various TNBC cells. Cantharidin is an effective ingredient in many clinical traditional Chinese medicine preparations, such as Delisheng injection, Aidi injection, Disodium cantharidinate and vitamin B6 injection. Previous studies showed that cantharidin had satisfactory pharmacological activity on a variety of tumors. In this study, we aimed to study the therapeutic potential of cantharidin for TNBC treatment by targeting EGFR, and expound its novel regulator miR-607. METHODS: The effect of cantharidin on breast cancer in vivo was evaluated by 4T1 mice model. Then the effects of cantharidin on TNBC cells was assessed by the MTT, colony formation, and AnnexinV-PE/7AAD staining. Cantharidin acts on EGFR were verified using the cell membrane chromatography, RT-PCR, Western blotting, MTT, and so on. Mechanistic studies were explored by dual-luciferase report assay, RT-PCR, western blotting, and immunofluorescence staining assay. RESULTS: Cantharidin inhibited TNBC cell growth and induce apoptosis by targeting EGFR. miR-607 was a novel EGFR regulator and exhibited suppressive functions on TNBC cell behaviors. Mechanistic study showed that cantharidin blocked the downstream PI3K/AKT/mTOR and ERK/MAPK signaling pathway. CONCLUSION: Our results revealed that cantharidin may be served as a potential candidate for TNBC treatment by miR-607-mediated downregulation of EGFR.

Homoharringtonine sensitizes pancreatic cancer to erlotinib by direct targeting and miRNA-130b-3p-mediated EphB4-JAK2-STAT3 axis.

OBJECTIVES: Pancreatic cancer (PC) is a very lethal malignancy with a scarcity of treatment options. Although erlotinib- and gemcitabine-based treatments have been approved for PC, their effectiveness is limited. The present study is aimed at exploring the molecular and epigenetic mechanisms of anticancer activities of homoharringtonine (HHT) and its interaction with erlotinib to develop a potential therapeutic strategy for PC. METHODS: The RT-qPCR, western blotting, immunofluorescence and expression-vectors and oligonucleotide transfection were employed to determine the expression characteristics of onco-factors. Anticancer activities were determined by MTT, colony forming, and flowcytometric analysis. Dual luciferase assay was conducted to confirm putative target of miR-130b-3p. In-vivo experiments were followed by immunohistochemical assay. KEY FINDINGS: The EphB4/JAK2/STAT3 pathway drives the growth and proliferation of PC through induction of prosurvival factors and cell cycle mediators. HHT directly and epigenetically via miR-130b-3p targets EphB4, leading to downregulation of JAK2/STAT3 pathway. The inactivation of STAT3 results in diminution of antiapoptotic factors and cell cycle mediators. HHT also enhances the anticancer activity of erlotinib. CONCLUSIONS: HHT demonstrates potential anticancer activities in PC by downregulating EphB4/JAK2/STAT3 signalling. HHT also produces synergistic effects with erlotinib.

Intelligent gold nanoparticles for malignant tumor treatment via spontaneous copper manipulation and on-demand photothermal therapy based on copper induced click chemistry.

The excessive copper in tumor cells is crucial for the growth and metastasis of malignant tumor. Herein, we fabricated a nanohybrid to capture, convert and utilize the overexpressed copper in tumor cells, which was expected to achieve copper dependent photothermal damage of primary tumor and copper-deficiency induced metastasis inhibition, generating accurate and effective tumor treatment. The nanohybrid consistsed of 3-azidopropylamine, 4-ethynylaniline and N-aminoethyl-N'-benzoylthiourea (BTU) co-modified gold nanoparticles (AuNPs). During therapy, the BTU segment would specifically chelate with copper in tumor cells after endocytosis to reduce the intracellular copper content, causing copper-deficiency to inhibit the vascularization and tumor migration. Meanwhile, the copper was also rapidly converted to be cuprous by BTU, which further catalyzed the click reaction between azido and alkynyl on the surface of AuNPs, resulting in on-demand aggregation of these AuNPs. This process not only in situ generated the photothermal agent in tumor cells to achieve accurate therapy avoiding unexpected damage, but also enhanced its retention time for sustained photothermal therapy. Both in vitro and in vivo results exhibited the strong tumor inhibition and high survival rate of tumor-bearing mice after application of our nanohybrid, indicating that this synergistic therapy could offer a promising approach for malignant tumor treatment. STATEMENT OF SIGNIFICANCE: The distinctive excessive copper in tumor cells is crucial for the growth and metastasis of tumor. Therefore, we fabricated intelligent gold nanoparticles to simultaneously response and reverse this tumorigenic physiological microenvironment for the synergistic therapy of malignant tumor. In this study, for the first time we converted and utilized the overexpressed Cu2+ in tumor cells to trigger intracellular click chemistry for tumor-specific photothermal therapy, resulting in accurate damage of primary tumor. Moreover, we effectively manipulated the content of Cu2+ in tumor cells to suppress the migration and vascularization of malignant tumor, resulting in effective metastasis inhibition.

Albendazole exerts an anti-hepatocellular carcinoma effect through a WWOX-dependent pathway.

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related deaths. The WW-domain containing oxidoreductase (WWOX) protein suppresses carcinogenesis and its absence is closely related to aggressive HCC phenotypes. In this study, by using SPR analysis, cell viability assay and xenograft mice models, we found that albendazole (ABZ), a safe and effective anthelmintic drug, exhibited the binding affinity with WWOX protein and potential inhibition effect on HCC cells in vitro and in vivo. Overexpression and knockdown of WWOX confirmed that the suppression of HCC by ABZ. Flow cytometric analysis, western blotting analysis and Co-IP were conducted to study the mechanism of ABZ. Our data showed that ABZ regulated the interaction between WWOX and its binding proteins including p53 and C-MYC. Furthermore, ABZ triggered p53-induced intrinsic apoptosis and suppressed EMT-mediated migration by C-MYC/Fibronectin axis. In addition, ∆NP73 expression was significantly inhibited by ABZ, which further sensitized p53-induced intrinsic apoptosis and cell cycle arrest. In summary, ABZ could suppress the proliferation and migration of HCC cells by regulating WWOX-dependent signaling pathway.

Targeting mitochondrial dysfunctions in pancreatic cancer evokes new therapeutic opportunities.

Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity of this cancer urgently demand the exploration of novel approaches for the development of effective therapeutic measures. Metabolic derangement is one of the hallmarks of cancers which restructures mitochondrial activities and biological pathways. Apart from their bioenergetic and biosynthetic functions, mitochondria are also implicated in a myriad of cellular functions including proliferation, differentiation, apoptosis, senescence, homeostasis, and other cell regulatory mechanisms. It has been noted that PC, like other types of cancers, exploits these activities in favor of tumor growth and survival by inducing mitochondrial dysfunctions such as mitochondrial-DNA mutation, metabolic enzyme modification, ROS generation, mitophagy, evasion of apoptosis, and mitochondrial biogenesis. During pancreatic carcinogenesis, a large number of onco-factors including Bcl-2 family proteins, NF-κB, HIFs, NRF2, NOX, MFNs, DRP1, DUSP6, Cyp-D, PARKIN, and others are dysregulated, resulting into reprogramming of metabolic pathways and cellular kinetics. Hence, targeted interventions in these metabolic derangements may present some effective anticancer approaches. The current review gives an insight into various mitochondrial disorders and their targetable molecules in PC which may provide certain novel opportunities in the pursuit of therapeutic development. Furthermore, we have also discussed certain treatment perspectives in PC based on specific mitochondrial activities.

Morpholine-Functionalized Multicomponent Metallacage as a Vector for Lysosome-Targeted Cell Imaging.

Metallacages with suitable cavities and specific functions are promising delivery vectors in biological systems. Herein, we report a morpholine-functionalized metallacage for lysosome-targeted cell imaging. The efficient host-guest interactions between the metallacage and dyes prevent them from aggregation, so their emission in aqueous solutions is well maintained. The fluorescence quantum yield of these host-guest complexes reaches 74.40%. Therefore, the metallacage is further employed as a vector to deliver dyes with different emission colors (blue, green, and red) into lysosomes for targeted imaging. This research affords a type of vector for the delivery of various cargos toward biological applications, which will enrich the usage of metallacages in biomedical engineering.

Shuanghua decoction exerts anticancer activity by activating NLRP3 inflammasome via ROS and inhibiting NF-κB signaling in hepatocellular carcinoma cells.

BACKGROUND: Hepatocellular carcinoma (HCC) is a major subtype of liver cancer, with a high mortality rate, and close relation to chronic hepatitis. The components of the NLRP3 inflammasome are poorly expressed or even lost in HCC. Downregulation of the NLRP3 inflammasome expression significantly affects the clinical stages and pathological grade of HCC. According to previous research, Shuanghua decoction (SHD), a traditional folk prescription, has an inhibitory effect on nasopharyngeal cancer. PURPOSE: This study aimed to reveal the therapeutic potential of the traditional folk recipe, SHD and its demolition recipe for HCC, and to explore the underlying mechanism. METHODS: The effect of SHD and its demolition recipe on HCC cell biological behaviors was assessed using the MTT assay, colony formation, LDH release assay, KFluor-Edu staining, annexin V-FITC/PI staining assay, Hoechst staining, wound-healing assay, transwell assay, reactive oxygen species (ROS) release assay, HPLC, nude mice model, HE staining, IHC, western blot, and immunofluorescence staining in vitro and in vivo. RESULTS: SHD was found to inhibit HCC, and Oldenlandia and OP (Oldenlandia: Prunella spike = 2.5:1) were identified as the main ingredients that inhibited the proliferation and migration of HCC cells via the activation of the ROS-mediated NLRP3 inflammasome and inhibition of the NF-κB signaling pathway in vitro and in vivo. CONCLUSION: Overall, Chinese medicine theory and pharmacology research revealed that SHD, Oldenlandia and OP may be promising traditional Chinese medicine for the treatment of HCC.

Vandetanib drives growth arrest and promotes sensitivity to imatinib in chronic myeloid leukemia by targeting ephrin type-B receptor 4.

The oncogenic role of ephrin type-B receptor 4 (EPHB4) has been reported in many types of tumors, including chronic myeloid leukemia (CML). Here, we found that CML patients have a higher EPHB4 expression level than healthy subjects. EPHB4 knockdown inhibited growth of K562 cells (a human immortalized myelogenous leukemia cell line). In addition, transient transfection of EPHB4 siRNA led to sensitization to imatinib. These growth defects could be fully rescued by EPHB4 transfection. To identify an EPHB4-specific inhibitor with the potential of rapid translation into the clinic, a pool of clinical compounds was screened and vandetanib was found to be most sensitive to K562 cells, which express a high level of EPHB4. Vandetanib mainly acts on the intracellular tyrosine kinase domain and interacts stably with a hydrophobic pocket. Furthermore, vandetanib downregulated EPHB4 protein via the ubiquitin-proteasome pathway and inhibited PI3K/AKT and MAPK/ERK signaling pathways in K562 cells. Vandetanib alone significantly inhibited tumor growth in a K562 xenograft model. Furthermore, the combination of vandetanib and imatinib exhibited enhanced and synergistic growth inhibition against imatinib-resistant K562 cells in vitro and in vivo. These findings suggest that vandetanib drives growth arrest and overcomes the resistance to imatinib in CML via targeting EPHB4.

Intelligent Gold Nanoparticles with Oncogenic MicroRNA-Dependent Activities to Manipulate Tumorigenic Environments for Synergistic Tumor Therapy.

Tumorigenic environments, especially aberrantly overexpressed oncogenic microRNAs, play a critical role in various activities of tumor progression. However, developing strategies to effectively utilize and manipulate these oncogenic microRNAs for tumor therapy is still a challenge. To address this challenge, spherical nucleic acids (SNAs) consisting of gold nanoparticles in the core and antisense oligonucleotides as the shell are fabricated. Hybridized to the oligonucleotide shell is a DNA sequence to which doxorubicin is conjugated (DNA-DOX). The oligonucleotides shell is designed to capture overexpressed miR-21/miR-155 and inhibit the expression of these oncogenic miRNAs in tumor cells after tumor accumulation to manipulate genetic environment for accurate gene therapy. This process further induces the aggregation of these SNAs, which not only generates photothermal agents to achieve on-demand photothermal therapy in situ, but also enlarges the size of SNAs to enhance the retention time in the tumor for sustained therapy. The capture of the relevant miRNAs simultaneously triggers the intracellular release of the DNA-DOX from the SNAs to deliver tumor-specific chemotherapy. Both in vivo and in vitro results indicate that this combination strategy has excellent tumor inhibition properties with high survival rate of tumor-bearing mice, and can thus be a promising candidate for effective tumor treatment.

Selenium sulfide disrupts the PLAGL2/C-MET/STAT3-induced resistance against mitochondrial apoptosis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Overexpression of pleomorphic adenoma gene like-2 (PLAGL2) is associated with tumorigenesis. However, its function in HCC is unclear, and there are currently no anti-HCC drugs that target PLAGL2. Drug repositioning may facilitate the development of PLAGL2-targeted drug candidates. METHODS: The expression of PLAGL2 in HCC clinical tissue samples and HCC cell lines was analyzed by western blotting. The constructed HCC cell models were used to confirm the underlying function of PLAGL2 as a therapeutic target. Multiple in vitro and in vivo assays were conducted to determine the anti-proliferative and apoptosis-inducing effects of selenium sulfide (SeS2 ), which is clinically used for the treatment of seborrheic dermatitis and tinea versicolor. RESULTS: PLAGL2 expression was higher in HCC tumor tissues than in normal adjacent tissues. Its overexpression promoted the resistance of HCC cells of mitochondrial apoptosis through the regulation of the downstream C-MET/STAT3 signaling axis. SeS2 exerted significant anti-proliferative and apoptosis-inducing effects on HCC cells in a PLAGL2-dependent manner. Mechanistically, SeS2 suppressed C-MET/STAT3, AKT/mTOR, and MAPK signaling and triggered Bcl-2/Cyto C/Caspase-mediated intrinsic mitochondrial apoptosis both in vitro and in vivo. CONCLUSIONS: Our data reveal an important role of PLAGL2 in apoptosis resistance in HCC and highlight the potential of using SeS2 as a PLAGL2 inhibitor in patients with HCC.

Synergistic effect of toosendanin and regorafenib against cell proliferation and migration by regulating WWOX signaling pathway in hepatocellular carcinoma.

Regorafenib (RGF), a second-line multi-kinase inhibitor in the treatment of HCC (hepatocellular carcinoma) after sorafenib failure, exposes to the risk of drug resistance and subsequent progression of HCC patients. Toosendanin (TSN), a triterpenoid has presented excellent inhibition on several tumors. The purpose of this study is to investigate the inhibitory effect of the combination of TSN and RGF on HCC cells. We identified that TSN and RGF combination (TRC) synergistically inhibited the proliferation and migration of MHCC-97L cells. The upregulation of WWOX (WW-domain containing oxidoreductase) played a vital role in the HCC cell growth treated with TRC. TRC suppressed the phosphorylation of Stat3 and expression of DVL2, negatively regulated the activity of ß-catenin by promoting the phosphorylation of GSK3ß. In addition, the intranuclear proteins, including MMP2, MMP9, and C-MYC were significantly inhibited by TRC. The in vivo xenograft models confirmed that TRC effectually prevented the tumor growth through upregulating WWOX. Therefore, the treatment of TRC may be a potential solution of RGF resistance and promising therapeutic method in malignant HCC.

WWOX activation by toosendanin suppresses hepatocellular carcinoma metastasis through JAK2/Stat3 and Wnt/ß-catenin signaling.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Loss of WW-domain containing oxidoreductase (WWOX) has been proven to be associated with malignant metastasis in patients with HCC. In this study, by using a non-biased CRISPR knockout genetic screen targeting 19,050 human genes, we found that toosendanin (TSN) is a novel druggable WWOX candidate agonist for metastatic HCC patients. We also found that TSN exhibited significant anti-proliferative and anti-metastatic effects on HCC cells in a WWOX-dependent manner. Overexpression and knockdown of WWOX in vitro and in vivo confirmed that the suppression of HCC by TSN involved WWOX. TSN regulated Stat3, DVL2, and GSK3ß by transforming their interactions with WWOX as demonstrated by a Co-IP assay. TSN accelerated the degradation of ß-catenin by promoting the function of APC, AXIN1, CK1, and GSK3ß complex. Nuclear translocation of p-Stat3 Y705 and ß-catenin was impeded by the TSN-induced blockade of JAK2/Stat3 and Wnt/ß-catenin signaling, accompanied by the inhibition of MMPs and C-MYC.

Nanocomposite hydrogel with NIR/magnet/enzyme multiple responsiveness to accurately manipulate local drugs for on-demand tumor therapy.

Chemotherapy is one of the most commonly utilized approaches to treat malignant tumor. However, the well-controlled chemotherapy able to accurately manipulate local drugs for on-demand tumor treatment is still a challenge. Herein, a magnet and light dual-responsive hydrogel combining thermosensitive poly(N-acryloyl glycinamide) (PNAGA), doxorubicin (DOX) loaded and polyester (PE) capped mesoporous silica nanocarriers (MSNs) as well as Fe3O4 nanoparticles (Fe3O4 NPs) grafted graphene oxide (GO) was fabricated to address above issue. The Fe3O4 NPs and GO respectively serve as magnetothermal agent and photothermal agent to perform hyperthermia, meanwhile to generate chain motion of PNAGA with varying degrees under different conditions of magnetic field and/or NIR irradiation. This strategy not only allowed the gel-sol transition of the hydrogel by prior heating for tumor injection, but performed controllable release routes of DOX-MSNs-PE (DMP for short) nanocarriers to meet various requirements from different patients and the changing states of tumor. Furthermore, these escaped DMP nanocarriers could be taken by surrounding tumor cells, and then deliver their drug to these cells after rapid hydrolysis of the PE cap triggered by esterase, resulting in accurate chemotherapy. Both in vitro and in vivo results indicated that the PNAGA-DMP-Fe3O4@GO hydrogel combining well-controllable chemotherapy and hyperthermia can eliminate more than 90% tumor cells and effectively inhibit the tumor growth in mice model, demonstrating the great candidate of our hydrogel for accurate tumor therapy.

Novel diphenyl urea derivative serves as an inhibitor on human lung cancer cell migration by disrupting EMT via Wnt/ß-catenin and PI3K/Akt signaling.

Targeted anti-tumor small molecules are considered to be promising candidates for cancer treatment. The novel diphenyl urea derivative (DUD) was synthesized by the molecular docking based on the structure optimization of Taspine (a natural product). In this study, we explored the anti-metastatic potential of DUD for NSCLC in vitro. DUD significantly suppressed A549 cell migration by reversing EMT. The inhibition was reflected on upregulation of E-cadherin and downregulation of N-cadherin, vimentin, Snail and HIF-1α. Meanwhile, DUD inhibited the ß-catenin nuclear translocation by upregulating Axin and downregulating the expression of APC, CK1 and phosphorylation of GSK3ß, and simultaneously decreasing MMP9 and MMP13 expression. Moreover, it was associated with the downregulation of the PI3K/Akt/mTOR signaling. Furthermore, we used XAV939, an ß-catenin inhibitor, to verify the mechanism of DUD. These results suggested that DUD inhibited A549 cells migration by reversing EMT via Wnt/ß-catenin and PI3K/Akt signaling. DUD might be a potential therapeutic drug candidate for NSCLC treatment.

Chelerythrine hydrochloride inhibits proliferation and induces mitochondrial apoptosis in cervical cancer cells via PI3K/BAD signaling pathway.

Cervical cancer is the fourth most common female cancer worldwide, and drug targeted therapy plays a crucial role in delaying the progression of cervical carcinoma. Chelerythrine hydrochloride (CHE) is a natural alkaloid, which is a focal point in anti-tumor research. In this study, we investigated the effect of CHE on HeLa cells by using MTT assay, RTCA, and colony formation assay. In addition, the flow cytometric analysis, immunofluorescence staining assay and western blot analysis were performed to study the mechanism of CHE. The results showed that CHE exhibited a significant inhibitory effect in HeLa cells, and it could suppress the expression of PI3K subunits in a dose-dependent manner. Moreover, we found that the treatment of CHE further restrained the downstream AKT/mTOR and PKCα signaling. In addition, CHE induced mitochondrial apoptosis of HeLa cells by regulating the BCL-2 family member's expression. Immunofluorescence staining assay indicated that AIF and Cytochrome C were translocated from mitochondria to cytoplasm or nucleus, and notable changes in mitochondrial morphology of HeLa cells were also observed. Finally, the aberrant expression of CHE led to the mitochondrial apoptosis by upregulating the expression of APAF1, Cleaved-Caspase9, Cleaved-Caspase3, and Cleaved-PARP. In summary, CHE suppresses the proliferation of HeLa cells by trigging the mitochondrial apoptosis through the PI3K/BAD signaling pathway.

Homoharringtonine suppresses tumor proliferation and migration by regulating EphB4-mediated ß-catenin loss in hepatocellular carcinoma.

Overexpressed EphB4 conduce to tumor development and is regarded as a potential anticancer target. Homoharringtonine (HHT) has been approved for hematologic malignancies treatment, but its effect on hepatocellular carcinoma (HCC) has not been studied. This study elucidated HHT could restrain the proliferation and migration of HCC via an EphB4/ß-catenin-dependent manner. We found that the antiproliferative activity of HHT in HCC cells and tumor xenograft was closely related to EphB4 expression. In HepG2, Hep3B and SMMC-7721 cells, EphB4 overexpression or EphrinB2 Fc stimulation augmented HHT-induced inhibitory effect on cell growth and migration ability, and such effect was abrogated when EphB4 was knocked down. The similar growth inhibitory effect of HHT was observed in SMMC-7721 and EphB4+/SMMC-7721 cells xenograft in vivo. Preliminary mechanistic investigation indicated that HHT directly bound to EphB4 and suppressed its expression. Data obtained from HCC patients revealed increased ß-catenin expression and a positive correlation between EphB4 expression and ß-catenin levels. HHT-induced EphB4 suppression promoted the phosphorylation and loss of ß-catenin, which triggered regulation of ß-catenin downstream signaling related to migration, resulting in the reversion of EMT in TGF-ß-induced HepG2 cells. Collectively, this study provided a groundwork for HHT as an effective antitumor agent for HCC in an EphB4/ß-catenin-dependent manner.