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Fendiline Enhances the Cytotoxic Effects of Therapeutic Agents on PDAC Cells by Inhibiting Tumor-Promoting Signaling Events: A Potential Strategy to Combat PDAC

1
Department of Molecular Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA
2
Department of Tumor Biology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
3
Department of Drug Discovery, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
4
Department of Cellular and Molecular Physiology, Penn State Cancer Institute, 400 University Drive, Hershey, PA 17033, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Int. J. Mol. Sci. 2019, 20(10), 2423; https://doi.org/10.3390/ijms20102423
Received: 25 April 2019 / Revised: 10 May 2019 / Accepted: 12 May 2019 / Published: 16 May 2019
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders 2019)
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Abstract

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. View Full-Text
Keywords: pancreatic ductal adenocarcinoma (PDAC); intracellular signaling; fendiline; visudyne; tivantinib; gemcitabine; cell cycle; anchorage independent growth; migration; self-renewal pancreatic ductal adenocarcinoma (PDAC); intracellular signaling; fendiline; visudyne; tivantinib; gemcitabine; cell cycle; anchorage independent growth; migration; self-renewal
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MDPI and ACS Style

Alhothali, M.; Mathew, M.; Iyer, G.; Lawrence, H.R.; Yang, S.; Chellappan, S.; Padmanabhan, J. Fendiline Enhances the Cytotoxic Effects of Therapeutic Agents on PDAC Cells by Inhibiting Tumor-Promoting Signaling Events: A Potential Strategy to Combat PDAC. Int. J. Mol. Sci. 2019, 20, 2423.

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