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

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.

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

“…The clonogenic assay is considered a valuable in vitro assay for monitoring undifferentiated potential and anchorage-independent growth ( Rajendran and Jain, 2018 ). Given that Gem and AdipoR have been proved to act as effective agents in mitigating colony formation, we successively addressed the potential impact of combination AdipoR plus Gem on this PDAC feature ( Messaggio et al, 2017 ; Alhothali et al, 2019 ; Zhou et al, 2019 ).…”

Co-Administration of Fendiline Hydrochloride Enhances Chemotherapeutic Efficacy of Cisplatin in Neuroblastoma Treatment

“…However, in these previous works, fendiline was studied as a possible anticancer drug being administered alone. In addition, further studies supported the possible use of fendiline to enhance the efficacy of specific anticancer molecules in combined therapies of pancreatic ductal adenocarcinoma cells [ 31 ].…”

New Zealand Rabbit Spermatozoa Concentration after Giving of Beluntas Leaf Tannin Extract (Pluchea indica)

“…Mekanisme kerja senyawa metabolit sekunder sebagai obat bekerja dengan 2 cara, yaitu melalui efek sitotoksik dan melalui efek hormonal yang menghambat laju metabolisme sel spermiogenesis dengan cara mengganggu keseimbangan sistem hormone (Herdiningrat, 2002). Efek sitotoksik bekerja dengan mengganggu motilitas sel (Alhothali et al, 2019;Hu et al, 2017;Klongkumnuankarn et al, 2015;Morein et al, 2020;X. Wang et al, 2019).…”