Signal transduction of vitamin K3 for pancreas cancer therapy

We characterized molecular mechanisms of vitamin K3 (VK3)-induced inhibition of proliferation to evaluate VK3 effectiveness in treating advanced pancreatic cancer. A novel endoscopic drug delivery system, ultrasound injection technique, was used to study local effects of VK3. VK3 inhibited pancreas cancer cell growth by rapid phosphorylation of growth factor receptor and cellular signal factors such as extracellular signal-regulated kinase. VK3 also activated apoptosis, and apoptosis inhibitor antagonized the apoptosis pathway without inhibiting cell growth. Thiol antioxidant treatment completely abrogated VK3-induced ERK but not JNK phosphorylation or inhibition of proliferation. Non-thiol antioxidant did not affect ERK phosphorylation or growth inhibitory actions. Arylation was considered the main mechanism of VK3-induced growth inhibition through ERK activation. VK3 may lead to favorable outcomes in the treatment of pancreatic tumors. Detection of ERK phosphorylation in tissue is important to predict VK3 effect. Endoscopic ultrasound-guided fine-needle injection may be beneficial for treating pancreatic cancer with VK3.

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Retrospective Clinical Study of Advanced Pancreatic Cancer Treated With Chemotherapy and Abdominal Hyperthermia

Journal of Global Oncology ◽

10.1200/jgo.2017.009985 ◽

2018 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Yu-Fei Fan ◽

Yuan Qin ◽

Ding-Gang Li ◽

David Kerr

Keyword(s):

Pancreatic Cancer ◽

Molecular Mechanisms ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Stage Iv ◽

Treatment Modalities ◽

Hyperthermia Treatment ◽

Regional Hyperthermia ◽

Retrospective Clinical Study ◽

Clinical Series

Purpose Hyperthermia is a mechanistically plausible partner with chemotherapy, although many of the underlying molecular mechanisms of this combination treatment are not yet properly understood. Preclinical studies suggest that there is potential synergy with gemcitabine and that provides the basis for retrospective analysis of a clinical series combining these treatment modalities for patients with advanced pancreatic cancer. Patients and Methods Twenty-nine chemotherapy-naive patients with locally advanced or metastatic pancreatic carcinoma with malignant ascites were treated with intraperitoneal cisplatin 30 mg/m2 and gemcitabine 800 to 1,000 mg/m2 intravenously on days 1, 8, and 15 every 28 days until tumor progression. Patients also received regional hyperthermia treatment (41 to 42°C) on the upper abdomen two times per week from days 1 to 21. Results In all, 83 cycles of chemotherapy were administered and were generally well tolerated. No patients had a complete response, 13 had a partial response, seven had stable disease, and 9 had progressive disease. Mean progression-free survival and overall survival were 119 ± 61days and 195 ± 98 days, respectively. Conclusion This study provides preliminary evidence that the treatment approach of combined systemic and intraperitoneal chemotherapy plus hyperthermia is well tolerated, is active, and has an acceptable survival profile for patients with stage IV pancreatic cancer and ascites.

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ANTXR1 Facilitates Tumor Growth in Glioma via Deactivating MAPK Signaling Pathway

10.21203/rs.3.rs-126784/v1 ◽

2020 ◽

Author(s):

Aijun Liang ◽

Chaoyang Zhou ◽

Jianzhong Zhang ◽

Jingxing Leng ◽

Bin Xi ◽

...

Keyword(s):

Cell Growth ◽

Glioma Cell ◽

Molecular Mechanisms ◽

Mapk Signaling ◽

Tumor Promoter ◽

Normal Brain ◽

Apoptosis Pathway ◽

Xenograft Models

Abstract Background: Gliomas are commonly known as primary brain tumors and associated with frequent recurrence and an unsatisfactory prognosis in despite of extensive research in the underlying molecular mechanisms. In this study, we aimed to examine the role of ANTXR1 in glioma tumorigenesis and explore its downstream regulatory mechanism. Methods: We detected overexpression of ANTXR1 in glioma cell lines (SHG-44 and U251) in comparison with those in normal brain tissues.Result: Glioma cell growth and migratory ability were dramatically impaired as a result of silencing ANTXR1 by shANTXR1 lentivirus. ANTXR1 blockade also accelerated cell apoptosis since ANTXR1 held back apoptosis via targeting G2 phrase during cell mitosis. In vivo xenograft models verified in vitro findings above that the solid tumors stripped from mice were much lighter and smaller after depletion of ANTXR1 than controls. We also mechanically probed the downstream pathways and disclosed that overexpression of ANTXR1 abrogated the levels of MAKP9 and apoptisis-related protein HTRA2, but augmenting CCND1 and CDK6 levels in glioma cells. Our findings allow us to demonstrate that ANTXR1 acts as a tumor promoter in glioma induction through attenuating MAPK9-mediated gene transcription and HTRA2-induced apoptisis but intensifying CCND1-mediated proliferation. Conclusion: Together, we declare that ANTXR1 plays an indispensable role in glioma tumorigenesis via deactivating MAPK signaling and apoptosis pathway but activating PI3K/AKT-mediated cell growth. Our study provide a valuable clue to targeting ANTXR1 as a molecular target and a promising anticancer agent in glioma clinical therapeutics.

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CX-5461 Inhibits Pancreatic Ductal Adenocarcinoma Cell Growth, Migration and Induces DNA Damage

Molecules ◽

10.3390/molecules24244445 ◽

2019 ◽

Vol 24 (24) ◽

pp. 4445 ◽

Cited By ~ 1

Author(s):

Btissame El Hassouni ◽

Giulia Mantini ◽

Benoît Immordino ◽

Godefridus J. Peters ◽

Elisa Giovannetti

Keyword(s):

Pancreatic Cancer ◽

Dna Damage ◽

Cell Growth ◽

Cancer Cells ◽

Ribosome Biogenesis ◽

Molecular Mechanisms ◽

Ductal Adenocarcinoma ◽

Cell Growth And Migration ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells

Background: Inhibition of ribosome biogenesis has recently emerged as a promising strategy for the treatment of metastatic tumors. The RNA polymerase I inhibitor CX-5461 has shown efficacy in a panel of cancer types and is currently being tested in clinical trials. However, further preclinical studies to unravel molecular mechanisms underlying the activity of this drug are warranted. Methods: In this study, we have investigated the effects of CX-5461 on cell growth and migration of pancreatic cancer cells by the sulforhodamine-B and wound healing assay, respectively. Furthermore, we assessed the expression of epithelial-to-mesenchymal transition (EMT) genes by qRT-PCR, while protein expression of DNA damage marker phospho-H2A.X was studied by Western blot and immunofluorescence. Results: CX-5461 inhibits pancreatic cancer cell growth in the nanomolar range and inhibits the migratory capability of the cells. Additionally, CX-5461 induced expression of EMT factor SNAI1 and caused DNA double-strand breaks as measured by increased expression of phospho-H2A.X. Conclusion: This study demonstrated that CX-5461 is active against pancreatic cancer cells and modulation of EMT factors, as well as increased expression of phospho-H2A.X, support further pre-/clinical investigations, including the analyses of these markers.

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