Sonodynamic Therapy Combined to 2-Deoxyglucose Potentiate Cell Metastasis Inhibition of Breast Cancer

Metastasis is a major dilemma of cancer therapy. It frequently occurs in breast cancer, which is the leading form of malignant tumor among females worldwide. Although there are therapies that provide a possible method for this challenge, such as chemotherapy, the tumoral metabolic pathway is unconventional and favors metastasis and proliferation. This magnifies the difficulty of treating breast cancer. In this study, we identified 2-deoxyglucose (2 DG) as an important glycolysis suppressor that can potentiate sonodynamic therapy (SDT) to inhibit migration and invasion. In addition, disruptions of the cell membrane microstructure were captured by a scanning electron microscope in cells treated with the co-therapy. Similarly, we detected blockages of the cell cycle process, using flow cytometry. Of note, we observed that hexokinase II (HK2), the rate-limiting enzyme of glycolysis, was notably uncoupled from the mitochondria in SDT + 2 DG co-therapy group. Furthermore, there was altered expression of HK2 and Glut1, which control glycolysis. Simultaneously, the in vivo results revealed that pulmonary metastasis was also seriously suppressed by SDT + 2 DG co-therapy. These results demonstrate this co-therapy is a promising strategy for breast cancer inhibition through metastasis and proliferation.     

Berberine nanoparticles for promising sonodynamic therapy of a HeLa xenograft tumour

Here, we show that berberine (BBR) nanoparticles (BBRNPs, ∼300 nm hydrodynamic diameter) are a promising sonosensitizer for cancer sonodynamic therapy (SDT). HeLa cells were cultured for in vitro investigation, and a HeLa xenograft tumor model was established with BALB/c nude mice (∼20 g, female) for in vivo study. Significant effects of BBRNP-mediated SDT were observed in both in vitro and in vivo experiments. Cell counting kit-8 (CCK-8) cell proliferation and cytotoxicity assays were performed to confirm if BBRNPs-SDT has cytotoxicity against HeLa cells in vitro. The mechanism for inhibition of tumor proliferation by BBRNPs-SDT was investigated via flow cytometry, photoluminescence spectroscopy, dynamic light scattering, scanning electron microscopy, ultrasonic contrast imaging, tumour pathological analysis, western blot and anatomical analysis. We identified two ongoing assumptive mechanisms. One is due to the tumor angioembolism effect, which blocks oxygen and nutrient supply in situ, leading to early-stage HeLa apoptosis. The other domino effect is due to ultrasonic energy-activated BBRNP cavitation and reactive oxygen species release, which leads to tumor vascular injury and finally induces HeLa apoptosis, resulting in tumour shrinkage. Both pathways synergistically helped with HeLa xenograft tumor supression. In conclusion, we posit that BBRNPs are a promising agent for tumor SDT.

Here we show that berberine (BBR) nanoparticles (BBRNPs, ∼300 nm hydrodynamic diameter) is a promising sonosensitizer for cancer sonodynamic therapy (SDT).     

Optical Glucose Analogs of Aminolevulinic Acid for Fluorescence-Guided Tumor Resection and Photodynamic Therapy

Purpose

We have developed and tested a novel conjugation of the clinically used prodrug aminolevulinic acid with 2-deoxyglucosamine as a novel probe (ALA-2DG) for fluorescence imaging and photodynamic therapy.

Procedures

ALA-2DG was successfully synthesized, and the mechanisms of probe uptake, PpIX synthesis, and photodynamic therapy efficacy were evaluated in vitro and in vivo.

Results

ALA-2DG led to PpIX synthesis in tumor cells in vitro and in tumor in vivo. Competitive and inhibitory assays in vitro showed a reduction of this PpIX synthesis that was not observed when cells were incubated with ALA itself, indicating that intracellular uptake of ALA-2DG occurs by GLUT-mediated active transport. Initial photodynamic therapy studies confirmed the efficacy of ALA-2DG as a photodynamic sensitizer.

Conclusions

The in vitro assays suggest that ALA-2DG is taken up by cells via glucose transporters. Initial studies in oral cancer demonstrated the applicability of ALA-2DG for in vivo imaging and its potential as an alternative to ALA-PpIX-based fluorescence diagnostics and photodynamic therapy, providing higher tumor specificity.     

The Combination of Glycolytic Inhibitor 2-Deoxyglucose and Microbubbles Increases the Effect of 5-Aminolevulinic Acid-Sonodynamic Therapy in Liver Cancer Cells

Sonodynamic therapy (SDT) overcomes the shortcoming of photodynamic therapy in the treatment of cancer. Previous studies indicated that the glycolysis inhibitor 2-deoxyglucose (2-DG) potentiated photodynamic therapy induced tumor cell death and microbubbles (MBs) improved the SDT performance. We hypothesized that the combination of 2-DG and MBs will increase the effect of 5-aminolevulinic acid (ALA)-SDT in HepG2 liver cancer cells. When cells were treated with 5-min ALA-SDT and 2-mmol/L 2-DG, the cell survival rate decreased to 73.0 ± 7.1% and 75.2 ± 7.9%, respectively. Furthermore, 2 mmol/L 2-DG increased 5-min ALA-SDT induced growth inhibition and augmented ALA-SDT induced cell apoptotic rate from 9.8 ± 0.7% to 17.4 ± 2.2%. In the combination group (2-DG and ALA-SDT group), HepG2 cells possessed typical apoptotic characters. 2-DG also increased ALA-SDT associated intracellular reactive oxygen species generation and loss of mitochondrial membrane potential. Moreover, SonoVue MBs had stimulatory function on cell viability inhibition, apoptosis, reactive oxygen species production and mitochondrial membrane potential loss for combination treatment. This study suggests a promising therapeutic strategy using a combination of 2-DG, MBs and ALA-SDT for treating liver cancer.     

Sonodynamically Induced Anti-tumor Effect of 5-Aminolevulinic Acid on Pancreatic Cancer Cells

Sonodynamic therapy (SDT), a promising modality for cancer treatment, involves the synergistic interaction of ultrasound and some chemical compounds termed sonosensitizers. However, its effect on pancreatic cancer cells remains unclear. In our study, we sought to identify the cytotoxic effects of ultrasound-activated 5-aminolevulinic acid on human pancreatic cancer Capan-1 cells. Cell viability was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) analysis; mitochondrial membrane potential was assessed using the fluorescent probe jc-1; apoptosis was evaluated by flow cytometry; cell morphology was investigated by scanning electron microscopy; apoptosis-related protein expression was analyzed by Western blot assay. We found that SDT significantly decreased the survival rate of cells, and this effect increased with 5-aminolevulinic acid concentration and ultrasound exposure time. The mechanism underlying the effect of SDT involves, in part, the induction of a conspicuous loss in mitochondrial membrane potential and, in part, the induction of apoptosis through upregulation of Bax expression, downregulation of Bcl-2 and increased activation of procaspase-3. These results indicate that the ultrasonically induced cell killing effect could be enhanced by 5-ALA and that the mitochondrial pathway might be involved in the cell damage process. We conclude that SDT is a promising new methodology for pancreatic cancer treatment.     

Ultrasound-induced reactive oxygen species generation and mitochondria-specific damage by sonodynamic agent/metal ion-doped mesoporous silica

Designing tumor microenvironment (TME)-specific active nanoparticles with minimum side effects for synergistic cancer therapy has become a hot topic in the recent decades. Aiming at further enhancing the therapeutic efficacy, an in situ-induced mitochondrial dysfunction is a very promising strategy. To achieve these goals, a nano-sono-chemodynamic agent denoted as TPP-Cu@HMS, which integrated hematoporphyrin monomethyl ether (HMME), mPEG-NHS, triphenylphosphonium (TPP)-decorated mesoporous silica (MS) and coordinatively bound Cu²⁺ ions for mitochondria-specific sonodynamic-chemodynamic therapy (SDT-CDT) of cancer, was designed. Upon the ultrasound (US) treatment, TPP-Cu@HMS can specifically target mitochondria and in situ generate ¹O₂ against cancer cells. Specifically, to overcome the short lifespan of ¹O₂, the released Cu²⁺ ions from TPP-Cu@HMS could act as a Fenton-like agent to convert endogenous H₂O₂ to ·OH in the acidic environment of cancer cells, disrupt the mitochondrial membrane potential and lead to mitochondrial disintegration, which could systematically enhance the therapeutic efficiency of SDT. Therefore, we highlight the current strategy as a promising prospect for cancer therapy.

Herein, we design tumor microenvironment specific active nano sono-chemodynamic agent for synergistic photodynamic–chemodynamic cancer therapy.     

Retracted Article: SNHG3 promotes proliferation and invasion by regulating the miR-101/ZEB1 axis in breast cancer

Background: Dysregulated lncRNA expression contributes to the pathogenesis of human tumors via the lncRNAs functioning as oncogenes or tumor suppressors. Small nucleolar RNA host gene 3 (SNHG3) was demonstrated to be upregulated in breast cancer cells. However, the detailed roles and molecular mechanism of SNHG3 in breast cancer are largely unknown. Methods: The expression of SNHG3, miR-101, and zinc finger E-box-binding protein 1 (ZEB1) in breast cancer tissues and cells was detected using qRT-PCR. The effects of SNHG3 on cell proliferation and invasion were evaluated using MTT, EdU, and cell invasion assays. The protein levels of Ki-67, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase MMP-2, and MMP-9 were analyzed using western blot analysis. A luciferase reporter assay and RNA immunoprecipitation (RIP) were performed to explore the interaction between SNHG3, ZEB1 and miR-101. A subcellular fractionation assay was used to detect the subcellular location of SNHG3. Xenograft tumor experiments were conducted to verify the role and mechanism of SNHG3 in breast cancer in vivo. Results: SNHG3 expression was upregulated in breast cancer tissues and correlated with poor prognosis. SNHG3 knockdown suppressed breast cancer cell proliferation and invasion, which was further demonstrated by high levels of proliferation marker proteins Ki-67/PCNA and metastasis-related proteins MMP-2/MMP-9. Additionally, SNHG3 was located in the cytoplasm of breast cancer cells. SNHG3 functioned as a molecular sponge for miR-101 in breast cancer cells. miR-101 was downregulated in breast cancer tissues and negatively correlated with SNHG3 expression. Moreover, ZEB1, a target of miR-101, was positively regulated by SNHG3 in breast cancer cells. ZEB1 mRNA expression was upregulated in breast cancer tissues and positively correlated with SNHG3 expression. Mechanistically, SNHG3 knockdown suppressed cell proliferation and invasion by upregulation of miR-101 and downregulation of ZEB1 expression in breast cancer cells in vitro and in vivo. Conclusion: SNHG3 promoted proliferation and invasion by regulating the miR-101/ZEB1 axis in breast cancer.

In the present study, we investigated the expression and functional roles of SNHG3 in breast cancer cells, as well as the underlying mechanism of SNHG3 involved in the progression of breast cancer in vitro and in vivo.     

Adaptive Antiviral Immunity Is a Determinant of the Therapeutic Success of Oncolytic Virotherapy

Oncolytic virotherapy, the selective killing of tumor cells by oncolytic viruses (OVs), has emerged as a promising avenue of anticancer research. We have previously shown that KM100, a Herpes simplex virus type-1 (HSV) deficient for infected cell protein 0 (ICP0), possesses substantial oncolytic properties in vitro and has antitumor efficacy in vivo, in part by inducing antitumor immunity. Here, we illustrate through T-cell immunodepletion studies in nontolerized tumor-associated antigen models of breast cancer that KM100 treatment promotes antiviral and antitumor CD8⁺ cytotoxic T-cell responses necessary for complete tumor regression. In tolerized tumor-associated antigen models of breast cancer, antiviral CD8⁺ cytotoxic T-cell responses against infected tumor cells correlated with the induction of significant tumoristasis in the absence of tumor-associated antigen-specific CD8⁺ cytotoxic T-cells. To enhance oncolysis, we tested a more cytopathic ICP0-null HSV and a vesicular stomatitis virus M protein mutant and found that despite improved in vitro replication, oncolysis in vivo did not improve. These studies illustrate that the in vitro cytolytic properties of OVs are poor prognostic indicators of in vivo antitumor activity, and underscore the importance of adaptive antiviral CD8⁺ cytotoxic T-cells in effective cancer virotherapy.     

Development of a Composite of Polypyrrole-Coated Carbon Nanotubes as a Sonosensitizer for Treatment of Melanoma Cancer Under Multi-Step Ultrasound Irradiation

Sonodynamic therapy (SDT) has established a novel route for treating solid cancers. Low-intensity ultrasound irradiation accompanied by a sonosensitizer has revealed remarkable advantages for cancer therapy such as targeted uptake, access to deeper tumors, insignificant side effects and invasiveness, compared with other therapeutic methods. In this study, we scrutinized synthesis and characterization of a polypyrrole-coated multi-walled carbon nanotubes composite (PPy@MWCNTs). PPy@MWCNTs can absorb ultrasound irradiation by both of its components, and it was introduced as a new sonosensitizer. The composite was characterized by field emission scanning electron microscopy (FESEM), and its ability to temperature elevation was explored. FESEM images revealed that PPy@MWCNTs comprised nanotubes of 36.3 ± 5.1 nm in diameter with up to several micrometer in length. Ultrasound irradiation at 1 MHz and 1.0 W cm⁻² for 60 s in four steps led to an efficient SDT in vitro (16.3 ± 2.8°C temperature increment for 250 μg mL⁻¹ of PPy@MWCNTs), in C540 (B16/F10) cell line and a melanoma tumor model in male balb/c mice. In vitro examinations revealed that PPy@MWCNTs represented a concentration-dependent cytotoxicity on multi-step ultrasound irradiation (a cell viability of 8.9% for 250 μg mL⁻¹ of PPy@MWCNTs). Histologic analyses and tumor volume decrement after 10 d revealed detrimental SDT effects of PPy@MWCNTs on tumors (75% necrosis and 50% decrement in tumor volume). Thermal effects and reactive oxygen species generation were the reasons of the working function of PPy@MWCNTs in SDT.     

Targeted Expression of miR-34a Using the T-VISA System Suppresses Breast Cancer Cell Growth and Invasion

Recurrence and metastasis result in a poor prognosis for breast cancer patients. Recent studies have demonstrated that microRNAs (miRNAs) play vital roles in the development and metastasis of breast cancer. In this study, we investigated the therapeutic potential of miR-34a in breast cancer. We found that miR-34a is downregulated in breast cancer cell lines and tissues, compared with normal cell lines and the adjacent nontumor tissues, respectively. To explore the therapeutic potential of miR-34a, we designed a targeted miR-34a expression plasmid (T-VISA-miR-34a) using the T-VISA system, and evaluated its antitumor effects, efficacy, mechanism of action, and systemic toxicity. T-VISA-miR-34a induced robust, persistent expression of miR-34a, and dramatically suppressed breast cancer cell growth, migration, and invasion in vitro by downregulating the protein expression levels of the miR-34a target genes E2F3, CD44, and SIRT1. In an orthotopic mouse model of breast cancer, intravenous injection of T-VISA-miR-34a:liposomal complex nanoparticles significantly inhibited tumor growth, prolonged survival, and did not induce systemic toxicity. In conclusion, T-VISA-miR-34a lead to robust, specific overexpression of miR-34a in breast cancer cells and induced potent antitumor effects in vitro and in vivo. T-VISA-miR-34a may provide a potentially useful, specific, and safe-targeted therapeutic approach for breast cancer.     

3B,a novel photosensitizer,inhibits glycolysis and inflammation via miR-155-5p and breaks the JAK/STAT3/SOCS1 feedback loop in human breast cancer cells

Compared to normal cells, most cancer cells produce ATP by glycolysis under aerobic conditions rather than via the tricarboxylic acid cycle (TCA). This study is intended to determine whether 3B, a novel photosensitizer, can inhibit glycolysis and inflammation in breast cancer cells. We showed that 3B had the ability to repress glucose consumption as well as the generation of ATP, lactate and lactate dehydrogenase. 3B-PDT not only inhibited the expression of IL-1β and IL-6 but also affected the JAK-STAT3 inflammatory pathway in vitro. The present study showed that 3B featured a significant inhibitory effect on the expression of microRNA-155-5p and SOCS1 might serve as a target gene. In vivo studies revealed that 3B inhibited tumor growth and exhibited almost no side effects. Therefore, through the anti-glycolytic effect and breakage of the JAK/STAT3/SOCS1 feedback loop via miR-155-5p, 3B may potentially serve as a potential therapeutic agent against breast cancer.     

Solvothermal synthesis of Nb-doped TiO2 nanoparticles with enhanced sonodynamic effects for destroying tumors

Titania (TiO₂) nanomaterials have been proved to be biocompatible sonosensitizers for sonodynamic therapy (SDT) of various cancer cells, while they suffer from weak sonodynamic effects due to fast combination of excited carriers. In this work, to improve the therapeutic efficiency, we prepared PEGylated Nb-doped TiO₂ (TiO_2−x:Nb) nanoparticles by a simple solvothermal method and a subsequent surface modification process. The TiO_2−x:Nb nanoparticles exhibited an average size of 11 nm and a polydisperse index of 0.12. The Nb doping had no obvious effect on the phase of TiO₂ matrixes but released electrons to the conduction band of TiO₂, resulting in high concentrations of deficiencies. As a result, the TiO_2−x:Nb nanoparticles exhibited a higher efficiency of singlet oxygen (¹O₂) generation than that of pure TiO₂ nanoparticles upon ultrasound irradiation. Importantly, the TiO_2−x:Nb nanoparticles had high biocompatibility similar to pure TiO₂ nanoparticles, while they could efficiently produce cytotoxic ¹O₂ to destroy cancer cells in vitro in comparison to the partially destroyed cancer cells by pure TiO₂ nanoparticles upon ultrasound irradiation. More importantly, the TiO_2−x:Nb nanoparticles displayed obvious tumor cellular injury in tumor-bearing mice in vivo through high SDT effects. Therefore, the synthesized PEGylated TiO_2−x:Nb nanoparticles in this study exhibited higher therapeutic effects of SDT than that of the pure TiO₂ nanoparticles, and the doping strategy would provide some insights for tuning traditional weak sonosensitizers into efficient ones.

TiO_2−x:Nb nanoparticles displayed obvious tumor cellular injury in tumor-bearing mice in vivo through high SDT effect.     

Targeting miR-21 for the Therapy of Pancreatic Cancer

Despite tremendous efforts worldwide from clinicians and cancer scientists, pancreatic ductal adenocarcinoma (PDA) remains a deadly disease for which no cure is available. Recently, microRNAs (miRNAs) have emerged as key actors in carcinogenesis and we demonstrated that microRNA-21 (miR-21), oncomiR is expressed early during PDA. In the present study, we asked whether targeting miR-21 in human PDA-derived cell lines using lentiviral vectors (LVs) may impede tumor growth. We demonstrated that LVs-transduced human PDA efficiently downregulated miR-21 expression, both in vitro and in vivo. Consequently, cell proliferation was strongly inhibited and PDA-derived cell lines died by apoptosis through the mitochondrial pathway. In vivo, miR-21 depletion stopped the progression of a very aggressive model of PDA, to induce cell death by apoptosis; furthermore, combining miR-21 targeting and chemotherapeutic treatment provoked tumor regression. We demonstrate herein for the first time that targeting oncogenic miRNA strongly inhibit pancreatic cancer tumor growth both in vitro and in vivo. Because miR-21 is overexpressed in most human tumors; therapeutic delivery of miR-21 antagonists may still be beneficial for a large number of cancers for which no cure is available.     

Synthesis and biological evaluation of indazole derivatives as anti-cancer agents

Several FDA approved small molecule anti-cancer drugs contain indazole scaffolds. Here, we report the design, synthesis and biological evaluation of a series of indazole derivatives. In vitro antiproliferative activity screening showed that compound 2f had potent growth inhibitory activity against several cancer cell lines (IC₅₀ = 0.23–1.15 μM). Treatment of the breast cancer cell line 4T1 with 2f inhibited cell proliferation and colony formation. 2f dose-dependently promoted the apoptosis of 4T1 cells, which was connected with the upregulation of cleaved caspase-3 and Bax, and downregulation of Bcl-2. 2f also decreased the mitochondrial membrane potential and increased the levels of reactive oxygen species (ROS) in 4T1 cells. Additionally, treatment with 2f disrupted 4T1 cells migration and invasion, and the reduction of matrix metalloproteinase metalloproteinase-9 (MMP9) and increase of tissue inhibitor matrix metalloproteinase 2 (TIMP2) were also observed. Moreover, 2f could suppress the growth of the 4T1 tumor model without obvious side effects in vivo. Taken together, these results identified 2f as a potential small molecule anti-cancer agent.

One of the synthesized indazole derivatives, 2f, displayed inhibitory activities against proliferation, migration and invasion of breast cancer cell line 4T1, with the potential of inducing cell apoptosis, and suppressing tumor growth in vivo.     

Sonodynamic Therapy for Malignant Glioma Using 220-kHz Transcranial Magnetic Resonance Imaging-Guided Focused Ultrasound and 5-Aminolevulinic acid

Sonodynamic therapy (SDT) is used to treat various malignancies and can be applied to brain tumors using a transcranial magnetic resonance imaging-guided focused ultrasound (TcMRgFUS) device. This study investigated the efficacy of 220-kHz TcMRgFUS combined with 5-aminolevulinic acid (5-ALA) on malignant glioma in vitro and in vivo. F98 cells were irradiated with focused ultrasound (FUS) (4000 J, 20 W, 240 s, 100% duty cycle, target medium temperature <40°C) after treatment with 200 µg/mL 5-ALA, and cell viability and apoptosis were evaluated with the water-soluble tetrazolium-1 assay, triple fluorescent staining and Western blot analysis 20 h later. The anti-tumor effects of 5-ALA combined with FUS (500 J, 18 W, 30 s, 100% duty cycle, 10 repeats, target tissue temperature ≤42°C) were assessed on the basis of changes in tumor volume determined by MRI and histopathological analysis before and after treatment. The FUS/5-ALA combination reduced cell viability by inducing apoptosis and suppressed tumor proliferation and invasion as well as angiogenesis in vivo, while causing minimal damage to normal brain tissue. SDT with 220-kHz TcMRgFUS and 5-ALA can be safely used for the treatment of malignant glioma.     

GOLGA2/GM130, cis-Golgi Matrix Protein,is a Novel Target of Anticancer Gene Therapy

Achievement of long-term survival of patients with lung cancer treated with conventional chemotherapy is still difficult for treatment of metastatic and advanced tumors. Despite recent progress in investigational therapies, survival rates are still disappointingly low and novel adjuvant and systemic therapies are urgently needed. A recently elucidated secretory pathway is attracting considerable interest as a promising anticancer target. The cis-Golgi matrix protein, GOLGA2/GM130, plays an important role in glycosylation and transport of protein in the secretory pathway. In this study, the effects of short hairpin RNA (shRNA) constructs targeting GOLGA2/GM130 (shGOLGA2) on autophagy and lung cancer growth were evaluated in vitro and in vivo. Downregulation of GOLGA2/GM130 led to induction of autophagy and inhibition of glycosylation in A549 cells and in the lungs of K-ras^LA1 mice. Furthermore, downregulation of GOLGA2/GM130 decreased angiogenesis and cancer cell invasion in vitro and suppressed tumorigenesis in lung cancer mice model. The tumor specificity of sequence targeting GOLGA2/GM130 was also demonstrated. Taken together, these results suggest that induction of autophagy by shGOLGA2 may induce cell death rather than cell survival. Therefore, downregulation of GOLGA2/GM130 may be a potential therapeutic option for lung cancer.     

A novel small-molecule YLT256 inhibits proliferation and induces apoptosis both in vitro and in vivo in solid tumors

Pancreatic carcinoma is a still unsolved health problem all over the world with poor prognosis and high mortality rate. YLT256, a novel synthesized chemical small inhibitor, displays potent antineoplastic activities via inducing apoptosis both in vitro and in vivo. In this study, we found that YLT256 showed growth inhibition against a broad spectrum of human cancer cell lines and pancreatic cancer cell line BxPc-3 was the most sensitive with an IC₅₀ of 0.42 μM. We also found YLT256 could induce apoptosis of BxPc-3 cells in a dose-dependent manner. Western blot analysis revealed that the occurrence of its apoptosis was associated with activation of caspases-3 and -9, up-regulation of pro-apoptotic Bak, and down-regulation of anti-apoptotic Bcl-2. Moreover, YLT256-treated resulted in changes of mitochondrial membrane potential (Δψm), and generation of reactive oxygen species (ROS). Furthermore, our data also revealed that YLT256 suppressed the growth of established tumor-bearing xenograft models without obvious side effects. Immunohistochemical analyses and TUNEL assay revealed an increase in cleaved caspase-3-positive cells and TUNEL-positive cells, a decrease in Ki67-positive cells upon YLT256. Together, all the results of present study provided evidence demonstrating that YLT256 could be a promising potential drug candidate for pancreatic cancer therapy.     

The combination of decitabine and aspirin inhibits tumor growth and metastasis in non-small cell lung cancer

ObjectiveCombination therapy has become the hallmark of lung cancer treatment, as it reduces the dosage intensity of individual drugs while increasing their efficacy. In the current study, we analyzed the combinatorial effect of decitabine and aspirin on non-small cell lung cancer (NSCLC) cell growth.MethodsIn this study, we investigated the combinatorial effect of decitabine and aspirin by MTT, colony formation, and Transwell assays. We also explored the underlying molecular mechanism via a series of in vitro and in vivo experiments.ResultsThe combination of decitabine and aspirin regulated cell viability and migration in vitro. Moreover, the combination therapy suppressed tumor cell growth by inhibiting the β-catenin/STAT3 signaling pathway. Our study also found that the regimen increased the phosphorylation of β-catenin and decreased the expression of STAT3 and β-catenin.ConclusionThe combined administration of decitabine and aspirin significantly reduced tumor growth compared with single-agent treatment and the control in vivo. The study results indicated that decitabine and aspirin could suppress NSCLC cell growth and metastasis via the β-catenin/STAT3 signaling pathway.     

超声响应性纳米粒子用于超声/光声成像引导下声动力/饥饿治疗小鼠结直肠癌

目的 制备载四苯基卟啉锌（TPZ）、葡萄糖氧化酶（GOD）与全氟戊烷的超声响应性纳米粒子（NP）TPZ-GOD NP,并评估其超声/光声双模态成像效果及介导声动力治疗（SDT）联合饥饿治疗小鼠结直肠癌的效果。方法 以薄膜水化法制备载TPZ及GOD的NP。观察TPZ-GOD NP基本特性,以紫外分光光度计检测其超声辐照下释放GOD量,以流式细胞仪检测结直肠癌CT-26细胞与TPZ-GOD NP共同孵育后细胞吞噬情况,于荧光显微镜下观察超声辐照后TPZ-GOD NP细胞毒性活性氧产生情况。检测TPZ-GOD NP增强体内外超声/光声双模态成像效果;观察TPZ-GOD NP介导SDT、饥饿治疗及二者联合对移植瘤小鼠模型的作用。结果 成功制备TPZ-GOD NP,颗粒呈球形,大小均一,平均粒径（262.10±62.92）nm。超声辐照后,GOD释放量随时间而增加。TPZ-GOD NP可被CT-26细胞吞噬,超声辐照后可产生大量细胞毒性活性氧;可发生液气相变,增强体内外超声造影效果。体外光声成像显示,TPZ-GOD NP光声信号值随浓度而呈线性增加。经尾静脉注射TPZ-GOD NP后,小鼠肿瘤区域内光声信号明显增强;SDT或饥饿治疗均可杀伤部分CT-26细胞,二者联合效果更佳。结论 制备TPZ-GOD NP具有超声响应性,可用于超声/光声双模态成像引导下声动力联合饥饿治疗小鼠结直肠癌。     

An Evaluation of 2-deoxy-2-[18F]Fluoro-D-Glucose and 3′-deoxy-3′-[18F]-Fluorothymidine Uptake in Human Tumor Xenograft Models

Purpose

The aim of this study is to assess the variability of 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]-FDG) and 3??-deoxy-3??-[¹⁸F]-fluorothymidine ([¹⁸F]-FLT) uptake in pre-clinical tumor models and examine the relationship between imaging data and related histological biomarkers.

Procedures

[¹⁸F]-FDG and [¹⁸F]-FLT studies were carried out in nine human tumor xenograft models in mice. A selection of the models underwent histological analysis for endpoints relevant to radiotracer uptake. Comparisons were made between in vitro uptake, in vivo imaging, and ex vivo histopathology data using quantitative and semi-quantitative analysis.

Results

In vitro data revealed that [1-¹⁴C]-2-deoxy-d-glucose ([¹⁴C]-2DG) uptake in the tumor cell lines was variable. In vivo, [¹⁸F]-FDG and [¹⁸F]-FLT uptake was highly variable across tumor types and uptake of one tracer was not predictive for the other. [¹⁴C]-2DG uptake in vitro did not predict for [¹⁸F]-FDG uptake in vivo. [¹⁸F]-FDG SUV was inversely proportional to Ki67 and necrosis levels and positively correlated with HKI. [¹⁸F]-FLT uptake positively correlated with Ki67 and TK1.

Conclusion

When evaluating imaging biomarkers in response to therapy, the choice of tumor model should take into account in vivo baseline radiotracer uptake, which can vary significantly between models.