Multifunctional iron-apigenin nanocomplex conducting photothermal therapy and triggering augmented immune response for triple negative breast cancer.

Triple negative breast cancer (TNBC) presents a formidable challenge due to its low sensitivity to many chemotherapeutic drugs and a relatively low overall survival rate in clinical practice. Photothermal therapy has recently garnered substantial interest in cancer treatment, owing to its swift therapeutic effectiveness and minimal impact on normal cells. Metal-polyphenol nanostructures have recently garnered significant attention as photothermal transduction agents due to their facile preparation and favorable photothermal properties. In this study, we employed a coordinated approach involving Fe3+ and apigenin, a polyphenol compound, to construct the nanostructure (nFeAPG), with the assistance of ß-CD and DSPE-PEG facilitating the formation of the complex nanostructure. In vitro research demonstrated that the formed nFeAPG could induce cell death by elevating intracellular oxidative stress, inhibiting antioxidative system, and promoting apoptosis and ferroptosis, and near infrared spectrum irradiation further strengthen the therapeutic outcome. In 4T1 tumor bearing mice, nFeAPG could effectively accumulate into tumor site and exhibit commendable control over tumor growth. Futher analysis demonstrated that nFeAPG ameliorated the suppressed immune microenvironment by augmenting the response of DC cells and T cells. This study underscores that nFeAPG encompasses a multifaceted capacity to combat TNBC, holding promise as a compelling therapeutic strategy for TNBC treatment.

miR-30c affects the pathogenesis of ulcerative colitis by regulating target gene VIP.

MicroRNAs play a crucial role in regulating the epithelial barrier and immune response, which are implicated in the pathogenesis of ulcerative colitis (UC). This study aimed to investigate the role and molecular mechanism of miR-30c in the pathogenesis of UC using a dextran sulfate sodium salt (DSS)-induced colitis model, which is similar to ulcerative colitis. Wild-type (WT) and miR-30c knockout (KO) mice were assigned to either control or DSS-treated groups to evaluate the influence of aberrant miR-30c expression on UC pathogenesis. The disease activity index, inflammatory factors, and the extent of pathological and histological damage in colon tissues were analyzed. The effect of miR-30c on vasoactive intestinal peptide (VIP) gene expression was validated through luciferase reporter assay, qRT-PCR, Western blotting, and immunohistochemistry. The results showed that miR-30c KO mice with DSS-induced colitis model showed more severe phenotypes: significantly higher disease activity indices, significant body weight loss, reduced length of the colon of mice, increased number of aberrant crypt structures, reduced mucus secretion, and significant differences in inflammatory factors. These findings suggested that the absence of miR-30c might promote DSS-induced colitis, and the targe-regulatory effect of miR-30c on VIP might play an important role in the development of colitis.

Auranofin inhibits the occurrence of colorectal cancer by promoting mTOR-dependent autophagy and inhibiting epithelial-mesenchymal transformation.

Colorectal cancer (CRC) is one of the world's most common and deadly cancers. According to GLOBOCAN2020's global incidence rate and mortality estimates, CRC is the third main cause of cancer and the second leading cause of cancer-related deaths worldwide. The US Food and Drug Administration has approved auranofin for the treatment of rheumatoid arthritis. It is a gold-containing chemical that inhibits thioredoxin reductase. Auranofin has a number of biological activities, including anticancer activity, although it has not been researched extensively in CRC, and the mechanism of action on CRC cells is still unknown. The goal of this research was to see how Auranofin affected CRC cells in vivo and in vitro . The two chemical libraries were tested for drugs that make CRC cells more responsive. The CCK-8 technique was used to determine the cell survival rate. The invasion, migration, and proliferation of cells were assessed using a transwell test and a colony cloning experiment. An electron microscope was used to observe autophagosome formation. Western blotting was also used to determine the degree of expression of related proteins in cells. Auranofin's tumor-suppressing properties were further tested in a xenograft tumor model of human SW620 CRC cells. Auranofin dramatically reduced the occurrence of CRC by decreasing the proliferation, migration, and invasion of CRC cells, according to our findings. Through a mTOR-dependent mechanism, auranofin inhibits the epithelial-mesenchymal transition (EMT) and induces autophagy in CRC cells. Finally, in-vivo tests revealed that auranofin suppressed tumor growth in xenograft mice while causing no harm. In summary, auranofin suppresses CRC cell growth, invasion, and migration. Auranofin inhibits the occurrence and progression of CRC by decreasing EMT and inducing autophagy in CRC cells via a mTOR-dependent mechanism. These findings suggest that auranofin could be a potential chemotherapeutic medication for the treatment of human CRC.

Cinobufagin exerts an antitumor effect in non-small-cell lung cancer by blocking STAT3 signaling.

Background: Non-small-cell lung cancer (NSCLC) is the most common histological subtype of lung cancer with significant morbidity and mortality rates worldwide. Cinobufagin, the primary component of Chansu and the major active ingredient of cinobufacini, has attracted widespread attention for its excellent anticancer effects, but its activity remains poorly characterized in NSCLC. Methods: The functions of cinobufagin treatment in anti-tumor was evaluated using various in vitro and in vivo assays. The change of STAT3 signaling by cinobufagin was analyzed using molecular docking, immunofluorescence technic and western blotting. Results: In vitro, we confirmed the inhibitory effect of cinobufagin on cell viability, proliferation, migration, epithelial-mesenchymal transition (EMT), as well as an apoptosis-inducing effect. The antitumor effects of cinobufagin were confirmed in vivo by measuring tumor growth in a mouse xenograft model. Cinobufagin was found to significantly inhibit the phosphorylation of signal transducer and activator of transcription 3 (STAT3) at tyrosine 705 (Y705) in a time- and concentration-dependent manner. Moreover, cinobufagin reversed IL-6-induced nuclear translocation of STAT3. Conclusions: Our study has demonstrated that cinobufagin exerts an antitumor effect in non-small-cell lung cancer by blocking STAT3 signaling, and cinobufagin is a promising candidate agent for NSCLC therapy.

Downregulation of CLDN6 inhibits cell migration and invasion and promotes apoptosis by regulation of the JAK2/STAT3 signaling pathway in hepatocellular carcinoma.

Background: High expression of CLDN6 in hepatocellular carcinoma (HCC) has been widely reported. During this research, CLDN6's effect on the infiltration, migration, and apoptosis of HCC cells was investigated. Methods: Initially, the knockdown and overexpression of CLDN6 in HCC cells were carried out by short interfering RNA (siRNA) and plasmid transfection. The transfection efficiency was detected by means of a quantitative real-time polymerase chain reaction (qRT-PCR) assay, immunofluorescence staining, and Western blot analysis. Transwell and wound-healing assays were employed for the detection of invasion and migration ability. CCK-8 assay and flow cytometry were utilized for the detection of apoptosis. Finally, analysis of the expression of pathway-related proteins (JAK2, STAT3, p-JAK2, and p-STAT3) and the regulation of apoptotic responses (by measurement of cleaved caspase-3, Bax, and Bcl-2 levels) was carried out. Results: When CLDN6 was knocked down, the cellular invasion and migration ability decreased, and apoptosis increased, which decreased p-JAK2, p-STAT3, and anti-apoptotic protein bcl-2 expression. Furthermore, an elevation was observed in cleaved caspase-3 and Bax expression levels. Contrarily, upon overexpression of CDLN6, the aforementioned experimental results were reversed. Conclusions: CLDN6 knockdown results in the inhibition of HCC cells' infiltration and migration and promotes apoptosis via downregulation of the JAK2/STAT3 signaling pathway.

ATB0,+-targeted nanoparticles initiate autophagy suppression to overcome chemoresistance for enhanced colorectal cancer therapy.

Oxaliplatin (OXA) resistance remains the major obstacle to the successful chemotherapy of colorectal cancer (CRC). As a self-protection mechanism, autophagy may contribute to tumor drug resistance, therefore autophagy suppression could be regarded as a possible treatment option in chemotherapy. Cancer cells, especially drug-resistant tumor cells, increase their demand for specific amino acids by expanding exogenous supply and up-regulating de novo synthesis, to meet the needs for excessive proliferation. Therefore, it is possible to inhibit cancer cell proliferation through pharmacologically blocking the entry of amino acid into cancer cells. SLC6A14 (ATB0,+) is an essential amino acid transporter, that is often abnormally up-regulated in most cancer cells. Herein, in this study, we designed oxaliplatin/berbamine-coloaded, ATB0,+-targeted nanoparticles ((O + B)@Trp-NPs) to therapeutically target SLC6A14 (ATB0,+) and inhibit cancer proliferation. The (O + B)@Trp-NPs utilize the surface-modified tryptophan to achieve SLC6A14-targeted delivery of Berbamine (BBM), a compound that is found in a number of plants used in traditional Chinese medicine, which could suppress autolysosome formation though impairing autophagosome-lysosome fusion. We verified the feasibility of this strategy to overcome the OXA resistance during colorectal cancer treatment. The (O + B)@Trp-NPs significantly inhibited the proliferation and decreased the drug resistance of resistant colorectal cancer cells. In vivo, (O + B)@Trp-NPs greatly suppressed the tumor growth in tumor-bearing mice, which is consistent with the in vitro data. This research offers a unique and promising chemotherapeutic treatment for colorectal cancer.

A Retrospective Analysis of the Efficacy of Endoscopic Variceal Ligation versus Endoscopic Tissue Adhesive Injection in the Treatment of Esophagogastric Variceal Bleeding.

BACKGROUND: The aim of the study was to investigate the effectiveness and safety of endoscopic variceal ligation (EVL) and endoscopic tissue adhesive injection (TAI) in the treatment of esophagogastric variceal bleeding (EVB). METHODS: A total of 245 patients with EVB who attended the First Affiliated Hospital of Bengbu Medical College from December 2017 to June 2021 were retrospectively collected. The participants were divided into the esophageal EVL (E-EVL) + gastric EVL (G-EVL) group (n = 103) and E-EVL + gastric TAI (G-TAI) group (n = 142), according to the procedure, comparing and assessing the clinical characteristics, laboratory results, operation time, rebleeding rate, efficacy, and complications. RESULTS: The E-EVL + G-EVL group had significantly less varicose vein diameter and operative time than the E-EVL + G-TAI group (p < 0.05). No statistical difference in the length of hospital stay between the two groups was noted (p > 0.05). The total rebleeding rate in the E-EVL + G-EVL group was 9.7%, whereas that of the E-EVL + G-TAI group was 11.9%; no statistical difference between the two groups was noted (p > 0.05). The overall effective rate of the E-EVL + G-EVL group was 90.21%, whereas that of the E-EVL + G-TAI group was 92.81%; no statistical difference between the two groups was observed (p > 0.05). The postoperative ulcer in the E-EVL + G-EVL group was smaller and more superficial than that in the E-EVL + G-TAI group, and the wound surface was smoother. CONCLUSION: Both EVL and TAI have good therapeutic effects on EVB. Furthermore, owing to its effectiveness in preventing rebleeding, no reduction in efficacy and no increase in complications, shortened operative time, smaller and superficial ulcer, and smoother wounds, gastric EVL is worthy of further clinical promotion.

Association between lactate-to-albumin ratio and 28-days all-cause mortality in patients with acute pancreatitis: A retrospective analysis of the MIMIC-IV database.

Objective: The Lactate-to-Albumin Ratio (LAR) has been applied as a new predictor in sepsis, heart failure, and acute respiratory failure. However, the role of LAR in predicting all-cause mortality in patients with acute pancreatitis has not been evaluated. Therefore, this study aimed to elucidate the correlation between LAR and 28-d all-cause mortality in patients with Acute Pancreatitis (AP). Methods: This study is a retrospective cohort study with the data from the MIMIC-IV (v1.0) database. We included adult patients with acute pancreatitis who were admitted to the intensive care unit in the study. The primary outcome was to evaluate the ability of LAR to predict death at 28-d of hospital admission in patients with AP. Results: A total of 539 patients with acute pancreatitis were included in this study. They were divided into a survival group (486 patients) and a death group (53 patients) according to whether they survived within 28-d of admission, and the mortality rate of patients within 28-d of admission was 9.8%. LAR was shown to be an independent predictor of all-cause mortality within 28-d of admission in patients with AP by multivariate COX regression analysis (HR, 1.59; 95% CI, 1.23 - 2.05; P < 0.001). the Area Under the Curve (AUC) value for LAR was 74.26% (95% CI: 67.02% - 81.50%), which was higher than that for arterial blood lactate (AUC = 71.25%) and serum albumin (AUC = 65.92%) alone. It was not inferior even when compared to SOFA (AUC = 75.15%). The optimal cutoff value for separating the survival and death groups according to Receiver Operating Characteristic (ROC) was found to be 1.1124. plotting Kaplan-Meier analysis with this cutoff value showed that patients with LAR ≥ 1.1124 had significantly higher all-cause mortality within 28-d of admission than those with LAR < 1.1124 (P < 0.001). The final subgroup analysis showed no significant interaction of LAR with each subgroup (P for interaction: 0.06 - 0.974). Conclusion: LAR can be used as an independent predictor of all-cause mortality in AP patients within 28-d of admission, with superior prognostic performance than arterial blood lactate or serum albumin alone.

Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy.

Reprogramed cellular metabolism is one of the most significant hallmarks of cancer. All cancer cells exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. The resultant enhanced availability of amino acids supports the reprogramed metabolic pathways and fuels the malignant growth and metastasis of cancers by providing energy and critical metabolic intermediates, facilitating anabolism, and activating signaling networks related to cell proliferation and growth. Therefore, pharmacologic blockade of amino acid entry into cancer cells is likely to have a detrimental effect on cancer cell growth. Here we developed a nanoplatform (LJ@Trp-NPs) to therapeutically target two transporters, SLC6A14 (ATB0,+) and SLC7A5 (LAT1), that are known to be essential for the sustenance of amino acid metabolism in most cancers. The LJ@Trp-NPs uses tryptophan to guide SLC6A14-targeted delivery of JPH203, a high-affinity inhibitor of SLC7A5. In the process, SLC6A14 is also down-regulated. We tested the ability of this strategy to synergize with the anticancer efficacy of lapatinib, an inhibitor of EGFR/HER1/HER2-assocated kinase. These studies show that blockade of amino acid entry amplifies the anticancer effect of lapatinib via interference with mTOR signaling, promotion of apoptosis, and suppression of cell proliferation and metastasis. This represents the first study to evaluate the impact of amino acid starvation on the anticancer efficacy of widely used kinase inhibitor.

Diosgenin inhibits the proliferation of gastric cancer cells via inducing mesoderm posterior 1 down-regulation-mediated alternative reading frame expression.

INTRODUCTION: Whether and how mesoderm posterior 1 (MESP1) plays a role in the proliferation of gastric cancer cells remain unclear. METHODS: The expression of MESP1 was compared in 48 human gastric cancer tissues and adjacent normal tissues. Knockdown of MESP1 was performed to investigate the role of MESP1 in the proliferation and apoptosis of BGC-823 and MGC-803 gastric cancer cells. Knockdown of alternative reading frame (ARF) was performed to study the role of ARF in the inhibitory effect of MESP1 knockdown on cell proliferation in gastric cancer cells. Mouse subcutaneous xenograft tumor model bearing BGC-823 cells was used to investigate the role of MESP1 in the growth of gastric tumor in vivo. The effect of seven active ingredients from T. terrestris on MESP1 expression was tested. The anti-cancer effect of diosgenin was confirmed in gastric cancer cells. MESP1 dependence of the anti-cancer effect of diosgenin was confirmed by MESP1 knockdown. RESULTS: MESP1 was highly expressed in human gastric cancer tissues (p < 0.05). MESP1 knockdown induced apoptosis and up-regulated the expression of ARF in gastric cancer cells (p < 0.05). Knockdown of ARF attenuated the anti-cancer effect of MESP1 knockdown (p < 0.05). In addition, MESP1 knockdown also suppressed tumor growth in vivo (p < 0.05). Diosgenin inhibits both mRNA and protein expression of MESP1 (p < 0.05). MESP1 knockdown attenuated the anti-cancer effect of diosgenin (p < 0.05). CONCLUSIONS: MESP1 promotes the proliferation of gastric cancer cells via inhibiting ARF expression. Diosgenin exerts anti-cancer effect through inhibiting MESP1 expression in gastric cancer cells.

Evaluation of bioactive glass scaffolds incorporating SrO or ZnO for bone repair: In vitro bioactivity and antibacterial activity.

A series of bioactive glass scaffolds doped with SrO or ZnO (0, 5, and 10 mol%) were synthesized by the foam replica and melting method. The thermodynamic evolution, phase composition, microstructure, ion release, in vitro bioactivity, and oxygen density of the scaffolds were characterized. The proliferation of murine long bone osteocyte Y4 cells was studied by cell culture. The survival rate of the BGs evaluated the antibacterial activity and Escherichia coli strains in co-culture. The results indicated that the process window decreases with the increase of dopants. All the samples have a pore structure size of 200-400 µm. When the scaffolds were immersed in simulated body fluid for 28 days, hydroxyapatite formation was not affected, but the degradation process was retarded. The glass network packing and ionic radii variations of the substitution ions control surface degradation, glass dissolution, and ion release. MTT results revealed that 5Sr-BG had a significant effect on promoting cell proliferation and none of the BGs were cytotoxicity. Sr-BGs and Zn-BGs exhibited significantly inhibited growth against E. coli bacterial strains. Generally, these results showed the 5Sr-BG scaffold with high vitro bioactivity, cell proliferation, and antibacterial property is an important candidate material for bone tissue regeneration and repair.

Dual Targeting EGFR and STAT3 With Erlotinib and Alantolactone Co-Loaded PLGA Nanoparticles for Pancreatic Cancer Treatment.

Pancreatic cancer (PC) is one of the most common malignancies and also a leading cause of cancer-related mortality worldwide. Many studies have shown that epidermal growth factor receptor (EGFR) is highly expressed in PC, which provides a potential target for PC treatment. However, EGFR inhibitors use alone was proven ineffective in clinical trials, due to the persistence of cellular feedback mechanisms which foster therapeutic resistance to single targeting of EGFR. Specifically, the signal transducer and activator of transcription 3 (STAT3) is over-activated when receiving an EGFR inhibitor and is believed to be highly involved in the failure and resistance of EGFR inhibitor treatment. Therein, we hypothesized that dual inhibition of EGFR and STAT3 strategy could address the STAT3 induced resistance during EGFR inhibitor treatment. To this end, we tried to develop poly (lactic-co-glycolic acid) (PLGA) nanoparticles to co-load Alantolactone (ALA, a novel STAT3 inhibitor) and Erlotinib (ERL, an EGFR inhibitor) for pancreatic cancer to test our guess. The loading ratio of ALA and ERL was firstly optimized in vitro to achieve a combined cancer-killing effect. Then, the ALA- and ERL-co-loaded nanoparticles (AE@NPs) were successfully prepared and characterized, and the related anticancer effects and cellular uptake of AE@NPs were studied. We also further detailly explored the underlying mechanisms. The results suggested that AE@NPs with uniform particle size and high drug load could induce significant pancreatic cancer cell apoptosis and display an ideal anticancer effect. Mechanism studies showed that AE@NPs inhibited the phosphorylation of both EGFR and STAT3, indicating the dual suppression of these two signaling pathways. Additionally, AE@NPs could also activate the ROS-p38 axis, which is not observed in the single drug treatments. Collectively, the AE@NPs prepared in this study possess great potential for pancreatic cancer treatment by dual suppressing of EGFR and STAT3 pathways and activating ROS-responsive p38 MAPK pathway.

Influence of periampullary diverticula on endoscopic retrograde cholangiopancreatography.

The present study aimed to explore the influence of the presence of periampullary diverticula (PAD) on the implementation of endoscopic retrograde cholangiopancreatography (ERCP). A total of 388 patients with pancreaticobiliary disease who underwent ERCP for the first time between January 2017 and December 2018 were included and they were divided into a PAD group (n=179) and non-PAD (N-PAD) group (n=209) according to the presence or absence of PAD. A logistic regression model was used to analyze the risk factors for PAD. The prevalence of PAD in males was higher than that in females [odds ratio (OR)=2.250, 95% CI: 1.670-3.801]. The prevalence of PAD in patients with bile duct stone was 57.92% and higher than that in patients without stone (OR=4.475, 95% CI: 2.932-7.679). The morbidity of PAD in elderly patients with bile duct stone was higher than in those without stone (OR=6.728, 95% CI: 3.790-11.943). Among the elderly patients, the constituent ratio of males in the PAD group was higher than that in the N-PAD group (χ2=13.543, P<0.001). The constituent ratio of patients who underwent endoscopic sphincterotomy (EST) was lower than that in the N-PAD group (χ2=10.800, P<0.001). In conclusion, the occurrence of PAD was high in elderly males and closely related to the occurrence of bile duct stones.

LncRNA XIST/miR-137 axis strengthens chemo-resistance and glycolysis of colorectal cancer cells by hindering transformation from PKM2 to PKM1.

BACKGROUND: Glycolysis was an essential driver of chemo-resistance in colorectal cancer (CRC), albeit with limited molecular explanations. OBJECTIVE: We strived to elucidate the involvement of lncRNA XIST/miR-137/PKM axis in chemo-tolerance and glycolysis of CRC. METHODS: Altogether 212 pairs of tumor tissues and adjacent normal tissues were collected from CRC patients. Moreover, human CRC epithelial cell lines, including HT29, SW480, SW620 and LoVo, were purchased in advance, and their activity was estimated after transfection of si-XIST or miR-137 mimic. Furthermore, 5-FU/cisplatin-resistance of CRC cells was determined through MTT assay, and glycolytic potential of CRC cells was appraised based on oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). RESULTS: Highly-expressed XIST were predictive of severe symptoms and unfavorable 3-year survival of CRC patients (P< 0.05). Besides, silencing of XIST not only diminished proliferative, migratory and invasive power of CRC cells (P< 0.05), but also enhanced sensitivity of CRC cells responding to 5-FU/cisplatin (P< 0.05). Glycolytic potency of CRC cells was also undermined by si-XIST, with decreased maximal respiration and maximal glycolytic capacity in the si-XIST group as relative to NC group (P< 0.05). Nevertheless, miR-137 mimic attenuated the facilitating effect of pcDNA3.1-XIST on proliferation, migration, invasion, 5-FU/cisplatin-resistance and glycolysis of CRC cells (P< 0.05). Ultimately, ratio of PKM2 mRNA and PKM1 mRNA, despite being up-regulated by pcDNA3.1-XIST, was markedly lowered when miR-137 mimic was co-transfected (P< 0.05). CONCLUSIONS: LncRNA XIST/miR-137 axis reinforced glycolysis and chemo-tolerance of CRC by elevating PKM2/PKM1 ratio, providing an alternative to boost chemo-therapeutic efficacy of CRC patients.

Mir-488 alleviates chemoresistance and glycolysis of colorectal cancer by targeting PFKFB3.

BACKGROUND: Considering the boosting effect of glycolysis on tumor chemoresistance, this investigation aimed at exploring whether miR-488/PFKFB3 axis might reduce drug resistance of colorectal cancer (CRC) by affecting glycolysis, proliferation, migration, and invasion of CRC cells. METHOD: Totally, 288 CRC patients were divided into metastasis/recurrence group (n = 107) and non-metastasis/recurrence group (n = 181) according to their prognosis about 1 year after the chemotherapy, and their 3-year overall survival was also tracked. Besides, miR-488 expression was determined in peripheral blood of CRC patients and also in CRC cell lines (ie, W620, HT-29, Lovo, and HCT116). The targeted relationship between miR-488 and PFKFB3 was predicted by Targetscan software and confirmed by dual-luciferase reporter gene assay. Moreover, glycolysis and drug tolerance of CRC cells lines were assessed. RESULTS: MiR-488 expression was significantly decreased in metastatic/recurrent CRC patients than those without metastasis/recurrence (P < .05), and lowly expressed miR-488 was suggestive of unfavorable 3-year survival, large tumor size, poor differentiation, in-depth infiltration, and advanced Duke stage of CRC patients (P < .05). Besides, CRC cell lines transfected by miR-488 mimic demonstrated decreases in glucose uptake and lactate secretion, increases in oxaliplatin/5-Fu-sensistivity, as well as diminished capability of proliferating, invading, and migratory (P < .05), which were reversible by extra transfection of pcDNA3.1-PFKFB3 (ie, miR-488 mimic + pcDNA3.1-PFKFB3 group). Finally, the mRNA level of PFKFB3 was down-regulated by miR-488 mimic in CRC cell lines after being targeted by it (P < .05). CONCLUSION: The miR-488/PFKFB3 axis might clinically refine chemotherapeutic efficacy of CRC, given its modifying glycolysis and metastasis of CRC cells.

Aloperine can reverse the cisplatin resistance of colorectal cancer cells via suppressing the HIF-1α/ERK signaling pathway.

Background: Aloperine can exert antitumor effects in colorectal cancer; however, it remains obscure whether aloperine can reverse the cisplatin resistance in colorectal cancer (CRC). Objective: To explore the roles of aloperine in the chemosensitivity of the DDP-resistant colorectal cancer cell line HT-29 (HT-29/DDP) and the related mechanism. Results: Aloperine can inhibit the proliferation of both HT-29 and HT-29/DDP cells in a dose-dependent manner; moreover, aloperine can significantly increase the sensitivity of HT-29/DDP cells to DDP; finally, HIF-1α and p-ERK was upregulated in HT-29/DDP cells and transient over-expression of HIF-1α has blocked aloperine+DDP induced anti-proliferative and pro-apoptotic effects on HT-29/DDP cells. Conclusion: We are reporting for the first time that aloperine can increase the sensitivity of HT-29/DDP cells to DDP and reverse cisplatin resistance via downregulating the HIF-1α /ERK signaling pathway.

Nanoparticle mediated codelivery of nifuratel and doxorubicin for synergistic anticancer therapy through STAT3 inhibition.

Chemotherapy is one of the most potent strategies to treat gastric cancer in clinic. However, the resistance of cancer cells to chemotherapeutics is a remarkable impediment to the treatment. Moreover, signal transducer and activator of transcription 3 (STAT3) is a critical transcriptional factor that over-activated in gastric cancer, and highly involved in the induction of chemoresistance. In this study, we developed poly (lactic-co-glycolic acid) (PLGA) nanoparticles to achieve the simultaneous codelivery of doxorubicin (DOX) and nifuratel (NIF, a novel STAT3 inhibitor) for enhanced cancer therapy. The synergistic effect of DOX and NIF against cancer cells was evaluated in gastric cancer cells. PLGA nanoparticles with an optimal ratio of DOX and NIF (DNNPs) were prepared and characterized. The cellular uptake and anticancer effects of DNNPs were investigated, and the underlying mechanisms were further explored. DNNPs presented as a spherical shape, provided sustained release profiles, and exhibited significantly increased uptake and cytotoxicity in gastric cancer cells. Mechanism studies showed that DNNPs significantly induced mitochondrial-dependent apoptosis and inhibited STAT3 phosphorylation, explaining the enhanced anticancer effect. These results suggested that DNNPs represented a promising strategy against gastric cancer by inhibiting the STAT3 pathway and amplifying apoptosis.

Carbidopa suppresses prostate cancer via aryl hydrocarbon receptor-mediated ubiquitination and degradation of androgen receptor.

Carbidopa, a peripheral decarboxylase inhibitor used with L-DOPA to treat Parkinson's disease, has attracted significant interest in recent years for its anticancer effect. Increasing evidence reveals that Carbidopa can inhibit cancer cell growth and induce apoptosis through aryl hydrocarbon receptor (AHR) in some cancers. However, the antitumor effect of Carbidopa in prostate cancer (PCa) is not fully understood. Androgen receptor (AR) plays a central role in PCa, even in advanced "castrate-resistant" disease. In the present study, we report that Carbidopa suppresses the growth of PCa by downregulating the protein expression of AR. Carbidopa inhibits proliferation and migration of LNCaP cells and promotes apoptosis, but has no effect on the AR-independent prostate cell line DU145. Carbidopa increases ubiquitination of AR in LNCaP cells. Several studies have shown that AHR can act as an E3 ubiquitin ligase and promote the proteasomal degradation of AR. Quantitative RT-PCR, immunofluorescence staining and immunoblotting assay demonstrate that AHR is induced and activated by Carbidopa, and the co-immunoprecipitation assay shows that AR interacts with AHR, firmly confirming that Carbidopa decreases AR protein level though AHR-induced proteasomal degradation. In addition, Carbidopa suppresses PCa growth in vivo when xenografted into immunocompromised mice. Carbidopa treatment increases AHR protein level and decreases AR protein level in tumor tissues. Taken together, our study implicates Carbidopa for the first time in effective suppression of prostate cancer via a mechanism, involving AHR-mediated proteasomal degradation of AR.

Synergism between SLC6A14 blockade and gemcitabine in pancreactic cancer: a 1H-NMR-based metabolomic study in pancreatic cancer cells.

Gemcitabine is the first-line chemotherapy for pancreatic cancer. To overcome the often-acquired gemcitabine resistance, other drugs are used in combination with gemcitabine. It is well-known that cancer cells reprogram cellular metabolism, coupled with the up-regulation of selective nutrient transporters to feed into the altered metabolic pathways. Our previous studies have demonstrated that the amino acid transporter SLC6A14 is markedly up-regulated in pancreatic cancer and that it is a viable therapeutic target. α-Methyltryptophan (α-MT) is a blocker of SLC6A14 and is effective against pancreatic cancer in vitro and in vivo. In the present study, we tested the hypothesis that α-MT could synergize with gemcitabine in the treatment of pancreatic cancer. We investigated the effects of combination of α-MT and gemcitabine on proliferation, migration, and apoptosis in a human pancreatic cancer cell line, and examined the underlying mechanisms using 1H-NMR-based metabolomic analysis. These studies examined the intracellular metabolite profile and the extracellular metabolite profile separately. Combination of α-MT with gemcitabine elicited marked changes in a wide variety of metabolic pathways, particularly amino acid metabolism with notable alterations in pathways involving tryptophan, branched-chain amino acids, ketone bodies, and membrane phospholipids. The metabolomic profiles of untreated control cells and cells treated with gemcitabine or α-MT were distinctly separable, and the combination regimen showed a certain extent of overlap with the individual α-MT and gemcitabine groups. This represents the first study detailing the metabolomic basis of the anticancer efficacy of gemcitabine, α-MT and their combination.

Ambidextrous Approach To Disrupt Redox Balance in Tumor Cells with Increased ROS Production and Decreased GSH Synthesis for Cancer Therapy.

An effective steady-state redox balance is maintained in cancer cells, allowing for protection against oxidative stress and thereby enhancing cell proliferation and tumor growth. Disruption of this redox balance would increase the cellular content of reactive oxygen species (ROS) and potentiate oxidative stress-induced cell death in tumor cells, thus representing an effective strategy for cancer treatment. Glutathione (GSH) is a major reducing agent, and its cellular levels are determined at least partly by the availability of cysteine via xCT (SLC7A11)-mediated entry of cystine into cells. We developed a nanoplatform using ZnO nanoparticles (NPs) as a carrier, loaded with salicylazosulfapyridine (SASP), and stabilized with DSPE-PEG, to form ultra-small NPs (SASP/ZnO NPs). The goal of this NP strategy is to disrupt the redox balance in cells by two mechanisms: increased generation of ROS and decreased synthesis of GSH. Such an approach would be effective in killing tumor cells. As expected, the SASP/ZnO NPs enhanced ROS production because of ZnO and impaired GSH synthesis because of SASP-induced inhibition of xCT (SLC7A11) transport function. As a consequence, treatment of tumor cells with SASP/ZnO NPs in vitro and in vivo resulted in a synergistic disruptive effect on redox balance in tumor cells and induced cell death and decreased tumor growth. This ambidextrous approach has potential in cancer therapy by combining two complementary pathways to disrupt the redox balance in tumor cells.