scholarly journals In vivo anticancer activity of a rhodium metalloinsertor in the HCT116 xenograft tumor model

2020 ◽  
Vol 117 (30) ◽  
pp. 17535-17542
Author(s):  
Stephanie D. Threatt ◽  
Timothy W. Synold ◽  
Jun Wu ◽  
Jacqueline K. Barton
Keyword(s):  
Chemotherapy Resistance ◽  
Tumor Model ◽  
Pharmacokinetic Studies ◽  
Xenograft Tumor ◽  
Delivery Methods ◽  
Dna Mutations ◽  
Anticancer Effects ◽  
Dna Mismatches ◽  
In Vivo Analysis

Mismatch repair (MMR) deficiencies are a hallmark of various cancers causing accumulation of DNA mutations and mismatches, which often results in chemotherapy resistance. Metalloinsertor complexes, including [Rh(chrysi)(phen)(PPO)]Cl2(Rh-PPO), specifically target DNA mismatches and selectively induce cytotoxicity within MMR-deficient cells. Here, we present an in vivo analysis of Rh-PPO, our most potent metalloinsertor. Studies with HCT116 xenograft tumors revealed a 25% reduction in tumor volume and 12% increase in survival with metalloinsertor treatment (1 mg/kg; nine intraperitoneal doses over 20 d). When compared to oxaliplatin, Rh-PPO displays ninefold higher potency at tumor sites. Pharmacokinetic studies revealed rapid absorption of Rh-PPO in plasma with notable accumulation in the liver compared to tumors. Additionally, intratumoral metalloinsertor administration resulted in enhanced anticancer effects, pointing to a need for more selective delivery methods. Overall, these data show that Rh-PPO inhibits xenograft tumor growth, supporting the strategy of using Rh-PPO as a chemotherapeutic targeted to MMR-deficient cancers.

scholarly journals m6A Modification-Mediated DUXAP8 Regulation of Malignant Phenotype and Chemotherapy Resistance of Hepatocellular Carcinoma Through miR-584-5p/MAPK1/ERK Pathway Axis

2021 ◽  
Vol 9 ◽  
Author(s):  
Zefeng Liu ◽  
Jin Lu ◽  
He Fang ◽  
Jiyao Sheng ◽  
Mengying Cui ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
Chemotherapy Resistance ◽  
Tumor Model ◽  
Mechanistic Study ◽  
Xenograft Tumor ◽  
Malignant Phenotype ◽  
Sorafenib Treatment ◽  
Xenograft Tumor Model

Hepatocellular carcinoma (HCC) has a poor prognosis due to its high malignancy, rapid disease progression, and the presence of chemotherapy resistance. Long-stranded non-coding RNAs (lncRNAs) affect many malignant tumors, including HCC. However, their mechanism of action in HCC remains unclear. This study aimed to clarify the role of DUXAP8 in regulating the malignant phenotype and chemotherapy resistance in HCC. Using an in vivo xenograft tumor model, the regulatory functions and mechanisms of lncRNA DUXAP8 in the progression and response of HCC to chemotherapy were explored. It was found that DUXAP8 was significantly upregulated in a patient-derived xenograft tumor model based on sorafenib treatment, which is usually associated with a relatively poor prognosis in patients. In HCC, DUXAP8 maintained its upregulation in the expression by increasing the stability of m6A methylation-mediated RNA. DUXAP8 levels were positively correlated with the proliferation, migration, invasion, and chemotherapy resistance of HCC in vivo and in vitro. In the mechanistic study, it was found that DUXAP8 competitively binds to miR-584-5p through a competing endogenous RNA (ceRNA) mechanism, thus acting as a molecular sponge for miR-584-5p to regulate MAPK1 expression, which in turn activates the MAPK/ERK pathway. These findings can provide ideas for finding new prognostic indicators and therapeutic targets for patients with HCC.

scholarly journals Circular RNA_CNST Promotes the Tumorigenesis of Osteosarcoma Cells by Sponging miR-421

2020 ◽  
Vol 29 ◽  
pp. 096368972092614
Author(s):  
Ji-Hai Wang ◽  
Xue-Jian Wu ◽  
Yong-Zhuang Duan ◽  
Feng Li
Keyword(s):  
Colony Formation ◽  
Specific Binding ◽  
Tumor Model ◽  
Gene Expression Omnibus ◽  
Pcr Analysis ◽  
Circular Rnas ◽  
Xenograft Tumor ◽  
Potential Biomarker

Circular RNAs (circRNAs) act crucial roles in the progression of multiple malignancies including osteosarcoma (OS). But, the underlying mechanisms by which hsa_circ_0017311 (circCNST) contributes to the tumorigenesis of OS remain poorly understood. Our present study aimed to explore the role and mechanisms of circCNST in OS tumorigenesis. The differentially expressed circRNAs were identified by the Gene Expression Omnibus database. The association of circCNST with clinicopathological features and prognosis in patients with OS was analyzed by RNA fluorescence in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (PCR) analysis. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation assays, and a xenograft tumor model were conducted to assess the role of circCNST in OS cells in vitro and in vivo. CircCNST-specific binding with miR-421 was confirmed by FISH, luciferase gene report, and RNA immunoprecipitation assays. As a result, we found that the expression levels of circCNST were dramatically increased in OS tissues and cell lines as compared with the adjacent normal tissues, and it was associated with tumor size and poor survival in OS patients. Knockdown of circCNST repressed cell viability, colony formation, and xenograft tumor growth, while restored expression of circCNST reversed these effects. Furthermore, circCNST was colocalized with miR-421 in the cytoplasm and acted as a sponge of miR-421, which attenuated circCNST-induced proliferation-promoting effects in OS cells by targeting SLC25A3. In conclusion, our findings demonstrate that circCNST promotes the tumorigenesis of OS cells by sponging miR-421, and provides a potential biomarker for patients with OS.

scholarly journals Circular RNA circ-CDYL sponges miR-1180 to elevate yes-associated protein in multiple myeloma

2020 ◽  
Vol 245 (11) ◽  
pp. 925-932 ◽  
Author(s):  
Fang Chen ◽  
Xiaohui Wang ◽  
Shuang Fu ◽  
Shaokun Wang ◽  
Yu Fu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Tumor Model ◽  
Circular Rna ◽  
Xenograft Tumor ◽  
Functional Assays ◽  
Xenograft Tumor Model ◽  
Therapeutic Possibility ◽  
Plasma Depletion ◽  
Potential Therapeutic Intervention

The covalently closed circular RNA has recently been proposed as a pivotal player in tumorigenesis. In the current study, we found that circ-CDYL was notably elevated in multiple myeloma tissue and plasma samples and had good diagnostic and prognostic efficacy. Functional assays showed that circ-CDYL enhanced the viability and DNA synthesis of multiple myeloma cells and inhibited apoptosis. Mechanically, cytoplasmic circ-CDYL was co-localized with miR-1180, and circ-CDYL absorbed miR-1180 to upregulate yes-associated protein (YAP), thereby facilitating multiple myeloma progression. Importantly, we further confirmed the existence of this circ-CDYL/miR-1180/YAP regulatory axis in vivo by using the xenograft tumor model. Taken together, our data demonstrate that circ-CDYL is novel promoter of multiple myeloma, and targeting circ-CDYL and its associated network implicates the therapeutic possibility for multiple myeloma patients. Impact statement Multiple myeloma (MM) is an extremely complex and heterogeneous disease, and its pathogenesis is poorly understood. Here, we described an important MM-related circular RNA (circRNA), circ-CDYL. It was remarkably increased in both MM cells and plasma. Depletion of circ-CDYL evidently stunted MM growth. Circ-CDYL could absorb miR-1180 and alleviated the repression of miR-1180 on YAP, leading to increased YAP expression, ultimately triggering MM uncontrolled growth. Therefore, our findings advance the understanding of MM pathogenesis, and also raise the possibility of considering circ-CDYL as a potential therapeutic intervention for MM.

scholarly journals mTORC2 promotes cell survival through c-Myc–dependent up-regulation of E2F1

2015 ◽  
Vol 211 (1) ◽  
pp. 105-122 ◽  
Author(s):  
Zhipeng Zou ◽  
Juan Chen ◽  
Anling Liu ◽  
Xuan Zhou ◽  
Qiancheng Song ◽  
...  
Keyword(s):  
Cell Survival ◽  
Tumor Model ◽  
Xenograft Tumor ◽  
In Vivo Experiments ◽  
Xenograft Tumor Model ◽  
Cancer Cell Survival ◽  
Consequent Reduction ◽  
Dependent Mechanism

Previous studies have reported that mTORC2 promotes cell survival through phosphorylating AKT and enhancing its activity. We reveal another mechanism by which mTORC2 controls apoptosis. Inactivation of mTORC2 promotes binding of CIP2A to PP2A, leading to reduced PP2A activity toward c-Myc serine 62 and, consequently, enhancement of c-Myc phosphorylation and expression. Increased c-Myc activity induces transcription of pri-miR-9-2/miR-9-3p, in turn inhibiting expression of E2F1, a transcriptional factor critical for cancer cell survival and tumor progression, resulting in enhanced apoptosis. In vivo experiments using B cell–specific mTORC2 (rapamycin-insensitive companion of mTOR) deletion mice and a xenograft tumor model confirmed that inactivation of mTORC2 causes up-regulation of c-Myc and miR-9-3p, down-regulation of E2F1, and consequent reduction in cell survival. Conversely, Antagomir-9-3p reversed mTORC1/2 inhibitor–potentiated E2F1 suppression and resultant apoptosis in xenograft tumors. Our in vitro and in vivo findings collectively demonstrate that mTORC2 promotes cell survival by stimulating E2F1 expression through a c-Myc– and miR-9-3p–dependent mechanism.

scholarly journals Enriched pharmacokinetic behavior and antitumor efficacy of thymoquinone by liposomal delivery

Nanomedicine ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. 641-656
Author(s):  
Hari Krishnareddy Rachamalla ◽  
Santanu Bhattacharya ◽  
Ajaz Ahmad ◽  
Kathyayani Sridharan ◽  
Vijay Sagar Madamsetty ◽  
...  
Keyword(s):  
Pancreatic Tumor ◽  
Tumor Model ◽  
Volume Of Distribution ◽  
Liposomal Formulation ◽  
Ethanol Injection ◽  
Anticancer Efficacy ◽  
Anticancer Effects ◽  
Systemic Bioavailability ◽  
Pharmacokinetic Behavior

Background: Thymoquinone (TQ) has potential anti-inflammatory, immunomodulatory and anticancer effects but its clinical use is limited by its low solubility, poor bioavailability and rapid clearance. Aim: To enhance systemic bioavailability and tumor-specific toxicity of TQ. Materials & methods: Cationic liposomal formulation of TQ (D1T) was prepared via ethanol injection method and their physicochemical properties, anticancer effects in orthotopic xenograft pancreatic tumor model and pharmacokinetic behavior of D1T relative to TQ were evaluated. Results: D1T showed prominent inhibition of pancreatic tumor progression, significantly greater in vivo absorption, approximately 1.5-fold higher plasma concentration, higher bioavailability, reduced volume of distribution and improved clearance relative to TQ. Conclusion: Encapsulation of TQ in cationic liposomal formulation enhanced its bioavailability and anticancer efficacy against xenograft pancreatic tumor.

CD142 plays a key role in the carcinogenesis of gastric adenocarcinoma by inhibiting BCL2-dependent autophagy

2021 ◽  
Author(s):  
Weifeng Xu ◽  
Beibei Chen ◽  
Dianshan Ke ◽  
Xiaobing Chen
Keyword(s):  
Cell Death ◽  
Malignant Tumors ◽  
Xenograft Tumor ◽  
Invasion And Migration ◽  
Autophagic Degradation ◽  
In Vivo Analysis ◽  
And Migration ◽  
Cancer Tissues

CD142 is expressed on the surface of multiple malignant tumors and contributes to various carcinogenesis. However, the role of CD142 in the pathogenesis of GAC remains unclear. This study aimed to investigate the role of CD142 in GAC carcinogenesis. Our results showed that CD142 expression was significantly increased in GAC cancer tissues, especially in those with significant invasion or metastasis. The invasion and migration of CD142-positive SNU16 cells were significantly increased compared with those of CD142-negative cells. Moreover, CD142 overexpression promoted the invasion and migration of SGC083 cells, but CD142 silencing was contrary. In addition, there was a positive correlation between CD142 expression of cancer tissues and serum IL-8 levels. CD142 overexpression promotes IL-8 production in SGC083 cells. In vivo analysis showed that the implantation of CD142-positive SNU16 cells promoted the growth of xenograft tumor and the production of IL-8. Mechanistically, CD142 silencing not only inhibited the expression of BCL2 and the interaction between BCL2 and Beclin1, but also promoted the autophagic response in SGC083. Furthermore, CD142 silencing-induced IL-8 degradation was recovered by treatment of autophagy inhibitor 3-MA. CD142 can inhibit autophagic cell death and the autophagic degradation of IL-8 in GAC, which exerts an effective effect on GAC carcinogenesis.

scholarly journals Construction of Hierarchical-Targeting pH-Sensitive Liposomes to Reverse Chemotherapeutic Resistance of Cancer Stem-like Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1205
Author(s):  
Shuang Ba ◽  
Mingxi Qiao ◽  
Li Jia ◽  
Jiulong Zhang ◽  
Xiuli Zhao ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Chemotherapy Resistance ◽  
Tumor Model ◽  
Ph Sensitive ◽  
Mitochondrial Targeting ◽  
Tumor Treatment ◽  
Chemotherapeutic Resistance ◽  
Xenograft Tumor Model ◽  
Tumor Region

Cancer stem-like cells (CSLCs) have been considered to be one of the main problems in tumor treatment owing to high tumorigenicity and chemotherapy resistance. In this study, we synthesized a novel mitochondria-target derivate, triphentlphosphonium-resveratrol (TPP-Res), and simultaneously encapsulated it with doxorubicin (Dox) in pH-sensitive liposomes (PSL (Dox/TPP-Res)), to reverse chemotherapeutic resistance of CSLCs. PSL (Dox/TPP-Res) was approximately 165 nm in size with high encapsulation efficiency for both Dox and TPP-Res. Cytotoxicity assay showed that the optimal synergistic effect was the drug ratio of 1:1 for TPP-Res and Dox. Cellular uptake and intracellular trafficking assay indicated that PSL (Dox/TPP-Res) could release drugs in acidic endosomes, followed by mitochondrial targeting of TPP-Res and nucleus transports for Dox. The mechanisms for reversing the resistance in CSLCs were mainly attributed to a synergistic effect for reduction of mitochondrial membrane potential, activation of caspase cascade reaction, reduction of ATP level and suppression of the Wnt/β-catenin pathway. Further, in vivo assay results demonstrated that the constructed liposomes could efficiently accumulate in the tumor region and possess excellent antineoplastic activity in an orthotopic xenograft tumor model with no evident systemic toxicity. The above experimental results determined that PSL (Dox/TPP-Res) provides a new method for the treatment of heterogenecity tumors.

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