Pseudopterosin and O-Methyltylophorinidine Suppress Cell Growth in a 3D Spheroid Co-Culture Model of Pancreatic Ductal Adenocarcinoma

Bioengineering

Irene Reimche¹  Jan Hänsel¹  Nicole Teusch¹  RussellG. Kerr²  RandallJ. Mrsny³  Bailu Xie³  Mert Erkan⁴  Haiqian Yu⁵  NiPutu Ariantari⁵  Peter Proksch⁵  Ibrahim Büdeyri⁶  Anne Gesell⁷  Janina Betz⁸  Vanessa Mundorf⁸ 

[1] Department of Biomedical Sciences, Institute of Health Research and Education, University of Osnabrück, 49074 Osnabrück, Germany;Department of Chemistry, and Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada;Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK;Department of Surgery, School of Medicine, Koç University,Sarıyer/İstanbul 34450, Turkey;Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany;Koç University Research Center for Translational Medicine, 34450 Istanbul, Turkey;Material and Chemical Characterization Facility, University of Bath, Bath BA2 7AY, UK;Technische Hochschule Köln, University of Technology, Arts and Sciences, 50678 Köln, Germany;

关键词: 3D co-culture;    spheroid;    stellate cells;    PDAC;    pancreatic ductal adenocarcinoma;    tumor microenvironment;   

DOI  :  10.3390/bioengineering7020057

来源: DOAJ

【 摘 要 】

Current therapies for treating pancreatic ductal adenocarcinoma (PDAC) are largely ineffective, with the desmoplastic environment established within these tumors being considered a central issue. We established a 3D spheroid co-culture in vitro model using a PDAC cell line (either PANC-1 or Capan-2), combined with stellate cells freshly isolated from pancreatic tumors (PSC) or hepatic lesions (HSC), and human type I collagen to analyze the efficiency of the chemotherapeutic gemcitabine (GEM) as well as two novel drug candidates derived from natural products: pseudopterosin (PsA-D) and O-methyltylophorinidine (TYLO). Traditional 2D in vitro testing of these agents for cytotoxicity on PANC-1 demonstrated IC₅₀ values of 4.6 (±0.47) nM, 34.02 (±1.35) µM, and 1.99 (± 0.13) µM for Tylo, PsA-D, and GEM, respectively; these values were comparable for Capan-2: 5.58 (±1.74) nM, 33.94 (±1.02) µM, and 0.41 (±0.06) µM for Tylo, PsA-D, and GEM, respectively. Importantly, by assessing the extent of viable cells within 3D co-culture spheroids of PANC-1 with PSC or HSC, we could demonstrate a significant lack of efficacy for GEM, while TYLO remained active and PsA-D showed slightly reduced efficacy: GEM in PANC-1/PSC (IC₅₀ = >100 µM) or PANC-1/HSC (IC₅₀ = >100 µM) spheroids, TYLO in PANC-1/PSC (IC₅₀ = 3.57 ± 1.30 nM) or PANC-1/HSC (IC₅₀ = 6.39 ± 2.28 nM) spheroids, and to PsA-D in PANC-1/PSC (IC₅₀ = 54.42 ± 12.79 µM) or PANC-1/HSC (IC₅₀ = 51.75 ± 0.60 µM). Microscopic 3D rendering supported these cytotoxicity outcomes, showing little or no morphological spheroid structure change during this period of rapid cell death. Our results support the use of this 3D spheroid co-culture in vitro model having a desmoplastic microenvironment for the identification of possible novel chemotherapeutic drug candidates for PDAC, such as TYLO and PsA-D.

【 授权许可】

Unknown