Fendiline Enhances the Cytotoxic Effects of Therapeutic Agents on PDAC Cells by Inhibiting Tumor-Promoting Signaling Events: A Potential Strategy to Combat PDAC
| Autor: | Geeta Iyer, Mevin Mathew, Marwa Alhothali, Srikumar Chellappan, Harshani R. Lawrence, Jaya Padmanabhan, Shengyu Yang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
endocrine system diseases
fendiline Cell Cycle Proteins tivantinib pancreatic ductal adenocarcinoma (PDAC) migration self-renewal Deoxycytidine lcsh:Chemistry chemistry.chemical_compound Mice 0302 clinical medicine Cell Movement Antineoplastic Combined Chemotherapy Protocols Medicine Neoplasm Metastasis lcsh:QH301-705.5 Spectroscopy YAP1 0303 health sciences Fendiline biology gemcitabine General Medicine Proto-Oncogene Proteins c-met visudyne Pyrrolidinones 3. Good health Computer Science Applications 030220 oncology & carcinogenesis Quinolines cell cycle Carcinoma Pancreatic Ductal Signal Transduction Cell Survival Antineoplastic Agents Catalysis Article Inorganic Chemistry 03 medical and health sciences Inhibitory Concentration 50 Pancreatic cancer Cell Line Tumor Animals Humans Physical and Theoretical Chemistry Tivantinib Molecular Biology Protein kinase B 030304 developmental biology Adaptor Proteins Signal Transducing Cell Proliferation anchorage independent growth Hippo signaling pathway business.industry Organic Chemistry CD44 intracellular signaling Verteporfin YAP-Signaling Proteins medicine.disease Phosphoproteins Pancreatic Neoplasms Disease Models Animal chemistry lcsh:Biology (General) lcsh:QD1-999 Cancer cell biology.protein Cancer research Carcinogens business |
| Zdroj: | International Journal of Molecular Sciences Volume 20 Issue 10 International Journal of Molecular Sciences, Vol 20, Iss 10, p 2423 (2019) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms20102423 |
| Popis: | The L-type calcium channel blocker fendiline has been shown to interfere with Ras-dependent signaling in K-Ras mutant cancer cells. Earlier studies from our lab had shown that treatment of pancreatic cancer cells with fendiline causes significant cytotoxicity and interferes with proliferation, survival, migration, invasion and anchorage independent growth. Currently there are no effective therapies to manage PDACs. As fendiline has been approved for treatment of patients with angina, we hypothesized that, if proven effective, combinatorial therapies using this agent would be easily translatable to clinic for testing in PDAC patients. Here we tested combinations of fendiline with gemcitabine, visudyne (a YAP1 inhibitor) or tivantinib (ARQ197, a c-Met inhibitor) for their effectiveness in overcoming growth and oncogenic characteristics of PDAC cells. The Hippo pathway component YAP1 has been shown to bypass K-Ras addiction, and allow tumor growth, in a Ras-null mouse model. Similarly, c-Met expression has been associated with poor prognosis and metastasis in PDAC patients. Our results presented here show that combinations of fendiline with these inhibitors show enhanced anti-tumor activity in Panc1, MiaPaCa2 and CD18/HPAF PDAC cells, as evident from the reduced viability, migration, anchorage-independent growth and self-renewal. Biochemical analysis shows that these agents interfere with various signaling cascades such as the activation of Akt and ERK, as well as the expression of c-Myc and CD44 that are altered in PDACs. These results imply that inclusion of fendiline may improve the efficacy of various chemotherapeutic agents that could potentially benefit PDAC patients. |
| Databáze: | OpenAIRE |
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