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1.
Clin. transl. oncol. (Print) ; 26(4): 951-965, Abr. 2024. graf
Article in English | IBECS | ID: ibc-VR-58

ABSTRACT

Background: Patients with pancreatic cancer have a dismal prognosis due to tumor cell infiltration and metastasis. Many reports have documented that EMT and PI3K–AKT–mTOR axis control pancreatic cancer cell infiltration and metastasis. Chloroxine is an artificially synthesized antibacterial compound that demonstrated anti-pancreatic cancer effects in our previous drug-screening trial. We have explored the impact of chloroxine on pancreatic cancer growth, infiltration, migration, and apoptosis. Methods: The proliferation of pancreatic cancer cell lines (PCCs) treated with chloroxine was assessed through real-time cell analysis (RTCA), colony formation assay, CCK-8 assay, as well as immunofluorescence. Chloroxine effects on the infiltrative and migratory capacities of PCCs were assessed via Transwell invasion and scratch experiments. To assess the contents of EMT- and apoptosis-associated proteins in tumor cells, we adopted Western immunoblotting as well as immunofluorescence assays, and flow cytometry to determine chloroxine effects on PCCs apoptosis. The in vivo chloroxine antineoplastic effects were explored in nude mice xenografts. Results: Chloroxine repressed pancreatic cancer cell growth, migration, and infiltration in vitro, as well as in vivo, and stimulated apoptosis of the PCCs. Chloroxine appeared to inhibit PCC growth by Ki67 downregulation; this targeted and inhibited aberrant stimulation of the PI3K–AKT–mTOR signaling cascade, triggered apoptosis in PCC via mitochondria-dependent apoptosis, and modulated the EMT to inhibit PCC infiltration and migration. Conclusions: Chloroxine targeted and inhibited the PI3K–AKT–mTOR cascade to repress PCCs growth, migration, as well as invasion, and triggered cellular apoptosis. Therefore, chloroxine may constitute a potential antineoplastic drug for the treatment of pancreatic cancer.(AU)


Subject(s)
Humans , Male , Female , Pancreatic Neoplasms , Carcinoma, Pancreatic Ductal , Antineoplastic Agents , Chloroquinolinols/pharmacokinetics , Chloroquinolinols/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism
2.
Clin Transl Oncol ; 26(4): 951-965, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37848695

ABSTRACT

BACKGROUND: Patients with pancreatic cancer have a dismal prognosis due to tumor cell infiltration and metastasis. Many reports have documented that EMT and PI3K-AKT-mTOR axis control pancreatic cancer cell infiltration and metastasis. Chloroxine is an artificially synthesized antibacterial compound that demonstrated anti-pancreatic cancer effects in our previous drug-screening trial. We have explored the impact of chloroxine on pancreatic cancer growth, infiltration, migration, and apoptosis. METHODS: The proliferation of pancreatic cancer cell lines (PCCs) treated with chloroxine was assessed through real-time cell analysis (RTCA), colony formation assay, CCK-8 assay, as well as immunofluorescence. Chloroxine effects on the infiltrative and migratory capacities of PCCs were assessed via Transwell invasion and scratch experiments. To assess the contents of EMT- and apoptosis-associated proteins in tumor cells, we adopted Western immunoblotting as well as immunofluorescence assays, and flow cytometry to determine chloroxine effects on PCCs apoptosis. The in vivo chloroxine antineoplastic effects were explored in nude mice xenografts. RESULTS: Chloroxine repressed pancreatic cancer cell growth, migration, and infiltration in vitro, as well as in vivo, and stimulated apoptosis of the PCCs. Chloroxine appeared to inhibit PCC growth by Ki67 downregulation; this targeted and inhibited aberrant stimulation of the PI3K-AKT-mTOR signaling cascade, triggered apoptosis in PCC via mitochondria-dependent apoptosis, and modulated the EMT to inhibit PCC infiltration and migration. CONCLUSIONS: Chloroxine targeted and inhibited the PI3K-AKT-mTOR cascade to repress PCCs growth, migration, as well as invasion, and triggered cellular apoptosis. Therefore, chloroxine may constitute a potential antineoplastic drug for the treatment of pancreatic cancer.


Subject(s)
Antineoplastic Agents , Chloroquinolinols , Pancreatic Neoplasms , Animals , Humans , Mice , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Movement , Cell Proliferation , Chloroquinolinols/pharmacology , Chloroquinolinols/therapeutic use , Mice, Nude , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism
3.
Curr Cancer Drug Targets ; 23(9): 731-741, 2023.
Article in English | MEDLINE | ID: mdl-37018533

ABSTRACT

INTRODUCTION: Pancreatic cancer is highly fatal and its incidence is rising worldwide. Its poor prognosis is attributed to a lack of effective diagnostic and therapeutic strategies. Dihydrotanshinone I (DHT), a phenanthrene quinone liposoluble compound from Salvia miltiorrhiza Bunge (Danshen), exerts anti-tumor effects by inhibiting cell proliferation, enhancing apoptosis, and inducing cell differentiation. However, its effects on pancreatic cancer are unclear. > Methods: The role of DHT in the growth of tumor cells was explored using real-time cell analysis (RTCA), colony formation assay, and CCK-8. The effects of DHT on tumor cells invasion as well as migration were assessed by Transwell and migration assays. Expressions of pro-apoptosis and metastasis factors in tumor cells were examined using western blot. Tumor apoptosis rates were studied using flow cytometry. The anticancer effect of DHT in vivo was assessed by tumor transplantation into nude mice. RESULTS: Our analyses show that DHT has a suppressive role in epithelial-mesenchymal transition (EMT), invasiveness, proliferation, as well as migratory ability of Patu8988 and PANC-1 cells via Hedgehog/Gli signaling. Moreover, it drives apoptosis via caspases/BCL2/BAX signaling. Experiments in nude mice transplanted with tumors have shown DHT to have anticancer effects in vivo. > Conclusion: Our data show that DHT effectively suppresses pancreatic cancer cell proliferation as well as metastasis, and induces apoptosis via Hedgehog/Gli signaling. These effects have been reported to be dose- and time-dependent. Therefore, DHT can be exploited as a potential treatment for pancreatic cancer.>.


Subject(s)
Pancreatic Neoplasms , Phenanthrenes , Animals , Mice , Apoptosis , Cell Line, Tumor , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Hedgehog Proteins/metabolism , Mice, Nude , Pancreatic Neoplasms/pathology , Phenanthrenes/pharmacology , Phenanthrenes/therapeutic use , Quinones/pharmacology , Quinones/therapeutic use , Signal Transduction , Humans , Pancreatic Neoplasms
4.
Front Pharmacol ; 12: 617714, 2021.
Article in English | MEDLINE | ID: mdl-33692690

ABSTRACT

Dimethyl fumarate (DMF) is an approved drug used in the treatment of multiple sclerosis (MS) and psoriasis therapy. Multiple studies have demonstrated other pharmacological activities of DMF such as an anti-cancer agent. In particular, studies have shown that DMF can modulate the NRF2/HO1/NQO1 antioxidant signal pathway and inactivate NF-κB to suppress the growth of colon and breast cancer cells, and induce cell death. In this study, we aimed to evaluate the anti-tumor activities of DMF in pancreatic cancer (PC) focusing on cell death as the predominant mechanism of response. We showed that both mitochondrial respiration and aerobic glycolysis were severely depressed following treatment with DMF and the effects could be abrogated by treatment with L-cysteine and N-acetyl-L-cysteine (NAC). Importantly, we verified that DMF induced metabolic crisis and that cell death was not related to alterations in ROS. Our data implied that MTHFD1 could be a potential downstream target of DMF identified by molecular docking analysis. Finally, we confirmed that MTHFD1 is up-regulated in PC and overexpression of MTHFD1 was negatively related to outcomes of PC patients. Our data indicate that DMF induces metabolic crisie to suppress cell growth and could be a potential novel therapy in the treatment of PC.

5.
Mol Ther Nucleic Acids ; 23: 215-216, 2021 Mar 05.
Article in English | MEDLINE | ID: mdl-33376628

ABSTRACT

[This corrects the article DOI: 10.1016/j.omtn.2019.05.026.].

6.
Mol Ther Nucleic Acids ; 17: 235-244, 2019 Sep 06.
Article in English | MEDLINE | ID: mdl-31272073

ABSTRACT

Small nuclear RNA host gene 7 (SNHG7), a novel long non-coding RNA (lncRNA), acts as an oncogene in cancers. However, whether SNHG7 is involved in hepatic stellate cell (HSC) activation during liver fibrosis is still unclear. In this study, upregulation of SNHG7 was found in vivo and in vitro during liver fibrosis. Silencing of SNHG7 led to the suppression of HSC activation, with a reduction in cell proliferation and collagen expression. SNHG7 knockdown also resulted in the suppression of liver fibrosis in vivo. Interestingly, miR-378a-3p was a target of SNHG7. SNHG7 and miR-378a-3p were co-located in the cytoplasm. Downregulation of miR-378a-3p blocked down the effects of loss of SNHG7 on HSC activation. Notably, SNHG7 could enhance Wnt/ß-catenin pathway activation to contribute to liver fibrosis, with an increase in T cell factor (TCF) activity and a reduction in P-ß-catenin level. It was found that miR-378a-mediated dishevelled segment polarity protein 2 (DVL2) was responsible for SNHG7-activated Wnt/ß-catenin pathway. DVL2 was confirmed as a target of miR-378a-3p. SNHG7-induced HSC activation was almost blocked down by DVL2 knockdown. Accordingly, enhanced Wnt/ß-catenin by SNHG7 was suppressed by loss of DVL2. Collectively, we demonstrate that SNHG7 reduces miR-378a-3p and attenuates its control on DVL2, leading to aberrant Wnt/ß-catenin activity, which contributes to liver fibrosis progression.

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