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.
Highlights
Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in the world
These cells were treated with indicated concentrations of gemcitabine (1 μM, 2.5 μM or 5 μM), tivantinib (1 μM or 2.5 μM), or visudyne (1 μM or 2 μM), alone or in combination with fendiline (1 μM, 2.5 μM, 5 μM, 10 μM or 15 μM) for 48 h and cell viability was assessed by MTT assay [40,53]
MiaPaCa2 cells were very sensitive to the treatment with 15 μM fendiline alone and addition of gemcitabine or tivantinib at this fendiline concentration did not show any further reduction in viability, but lower concentrations of fendiline showed an additive effect with gemcitabine and tivantinib in these cells as well (Figure 1B)
Summary
Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in the world. In 2016, it became the third leading cause of cancer deaths in the United States and it is expected to become the second leading cause by 2030 [1,2]. It is considered one of the deadliest and most aggressive cancers, with a 5-year survival rate of only 7% [3,4]. Though treatment with FOLFIRINOX and gemcitabine/nab-Paclitaxel combination improves survival, long-term survival is still poor and additional therapies are being sought out to effectively manage PDACs [5,10,11]
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