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Nintedanib

Manufactured by Boehringer Ingelheim
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Nintedanib is a multi-kinase inhibitor laboratory product developed by Boehringer Ingelheim. It targets various receptor tyrosine kinases involved in the pathogenesis of diseases.

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Lab products found in correlation

Rpmi 1640 medium, by Merck Group (1 mentions) Wst 1, by Merck Group (1 mentions) Kato 3, by American Type Culture Collection (1 mentions) Snu 5, by American Type Culture Collection (1 mentions) Tgf β1, by Boehringer Ingelheim (1 mentions) Sk mes 1, by American Type Culture Collection (1 mentions) Recombinant human tgf β1, by R&D Systems (1 mentions) Bleomycin, by Merck Group (1 mentions) Sterile normal saline solution, by Merck Group (1 mentions) Pirfenidone, by Santa Cruz Biotechnology (1 mentions) Anti rhoa, by Cell Signaling Technology (1 mentions) Anti myc, by Santa Cruz Biotechnology (1 mentions) Anti sma, by Abcam (1 mentions) Horseradish peroxidase hrp conjugated anti mouse and anti rabbit secondary antibodies, by Jackson ImmunoResearch (1 mentions) Human recombinant tgfβ, by R&D Systems (1 mentions) Basic fibroblast growth factor (bfgf), by R&D Systems (1 mentions) Roflumilast, by Boehringer Ingelheim (1 mentions) Culture insert 2 well, by Ibidi (1 mentions) C57bl 6 mice, by Charles River Laboratories (1 mentions) Pirfenidone, by Roche (1 mentions)

15 protocols using nintedanib

1

Cell Culture Protocols for Gastric Cancer

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The human GAC cell lines KATO-III and SNU-5 were purchased from the American Type Culture Collection (ATCC, Rockville, MD). Human GAC cell line MKN-45 was purchased from Creative Bioarray (Shirley, NY). Cell lines were authenticated by ATCC (KATO-III, SNU-5) or Creative Bioarray (MKN-45) and were routinely screened to ensure the absence of mycoplasma contamination (InvivoGen, San Diego, CA). The characteristics of these GAC cell lines are presented in Supplementary Table 1. Cells were cultured in RPMI 1640 medium (Sigma Chemical Co. St. Louis, MO) containing 10% or 20% FBS and maintained at 37°C in a humidified incubator with 5% CO2 and 95% air. Human gastric fibroblasts were purchased from ScienCell Research Laboratories (Carlsbad, CA) and cultured in a fibroblast specialty medium. Cytotoxic agents 5-FU, epirubicin (Epi), oxaliplatin (Oxa), docetaxel (Doc) and irinotecan (Iri) were purchased from the pharmacy at the Goshen Center for Cancer Care (Goshen, IN). Nintedanib was obtained from Boehringer Ingelheim Pharmaceuticals. The cell proliferation reagent WST-1 was purchased from Sigma-Aldrich.
Awasthi N., Schwarz M.A., Kaurich Q., Zhang C., Hilberg F, & Schwarz R.E. (2023). Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models. Frontiers in Oncology, 13, 1145999.
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2

Fibroblast Activation and Lung Cancer Interaction

Cited 2 times
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Fibroblast experiments were carried out with serum‐free DMEM.
17 (link) Fibroblasts from randomly selected patients were immortalized by transducing hTERT expression.
15 (link) Unless otherwise indicated, all fibroblasts were seeded on 0.1% collagen (Sigma) coated tissue culture plates and stimulated with 2.5 ng/mL recombinant human TGF‐β1 (R&D Systems) for 3 days to regain their activated phenotype observed in patient samples,
7 (link),
22 (link) which is partially lost in culture.
23 (link) This TGF‐β1 concentration is comparable to the average concentration found in the bronchoalveolar lavage fluid of lung cancer patients.
24 (link) In some experiments, fibroblasts were treated with TGF‐β1 in the presence of 2 μM nintedanib (Boehringer Ingelheim, provided by Frank Hilberg). Lung carcinoma cell lines derived from ADC (H1437, H23) or SCC (H520, SK‐MES‐1) patients (ATCC) were used in growth and invasion assays. Cancer cells were cultured in a RPMI‐based medium.
17 (link) Further details in Data S1.
Duch P., Díaz‐Valdivia N., Gabasa M., Ikemori R., Arshakyan M., Fernández‐Nogueira P., Llorente A., Teixido C., Ramírez J., Pereda J., Chuliá‐Peris L., Galbis J.M., Hilberg F., Reguart N., Radisky D.C, & Alcaraz J. (2024). Aberrant TIMP‐1 production in tumor‐associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma. Cancer Science, 115(5), 1505-1519.
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3

Nintedanib Attenuates Bleomycin-Induced Lung Injury

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Nintedanib was administered once daily through gavage at 30, 60 and 100 mg/kg for 5 days before MV (Boehringer Ingelheim, Biberach, Germany) 21. The mice received a single dosage of 0.075 units of bleomycin in 100 μl of sterile normal saline solution intratracheally (Sigma‐Aldrich, St. Louis, MO, USA) and were ventilated 5 days after the administration of bleomycin 13.
Li L., Kao K., Liu Y., Lin C., Chen N., Lee C., Wang C, & Yang C. (2017). Nintedanib reduces ventilation‐augmented bleomycin‐induced epithelial–mesenchymal transition and lung fibrosis through suppression of the Src pathway. Journal of Cellular and Molecular Medicine, 21(11), 2937-2949.
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4

Antibody-based Analysis of Fibrosis Regulators

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The following antibodies were used: anti-FN (Chen et al., 1978 (link)); anti-collagen I, anti-Erk2 (Santa Cruz Biotechnology); anti-SMA (Abcam); anti-RhoA (Cell Signaling), anti-p190RhoGAP (Cell Signaling); anti-Rnd3 (Millipore); anti-Rnd1 (abCam); anti-Rnd2 (abCam); anti-myc (Santa Cruz) and horseradish peroxidase (HRP)-conjugated anti-mouse and anti-rabbit secondary antibodies (Jackson ImmunoResearch). IPF drugs pirfenidone (1 mM) (Santa Cruz Biotechnology) and nintedanib (1 µM) (Boehringer) were used. All other reagents were from Sigma-Aldrich unless otherwise noted.
Monaghan-Benson E., Wittchen E.S., Doerschuk C.M, & Burridge K. (2018). A Rnd3/p190RhoGAP pathway regulates RhoA activity in idiopathic pulmonary fibrosis fibroblasts. Molecular Biology of the Cell, 29(18), 2165-2175.
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5

Nintedanib in Advanced Solid Tumors

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The study was conducted in accordance with the Declaration of Helsinki, International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS), the Belmont Report, and the U.S. Common Rule. All patients provided a written informed consent approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board. Nintedanib was provided by Boehringer Ingelheim GmbH. The senior academic authors had full access to all clinical and molecular data collected during the study and had final responsibility for the decision to submit the manuscript.
Won E., Basunia A., Chatila W.K., Hechtman J.F., Chou J.F., Ku G.Y., Chalasani S.B., Boyar M.S., Goldberg Z., Desai A.M., Tuvy Y., Berger M.F., Tang L., Kelsen D.P., Schattner M., Ilson D.H., Capanu M., Solit D.B., Schultz N, & Janjigian Y.Y. (2019). Efficacy of combined VEGFR1–3, PDGFα/β, and FGFR1–3 blockade using nintedanib for esophagogastric cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 25(13), 3811-3817.
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6

Nintedanib Modulates CCL4-Induced Liver Fibrosis

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Nintedanib 30 and 60 mg/kg/day (provided by Boehringer Ingelheim Pharma GmbH & Co. KG) was administered once daily by oral gavage. Administration volume was 10 mL/kg body weight. In the preventive protocol (Figure 1), there were four treatment groups (n = 10 per group): control (corn oil); CCL4 and oral vehicle; CCL4 and Nintedanib 30 mg/kg/day; and CCL4 and Nintedanib 60 mg/kg/day. In the therapeutic protocol, there were six treatment groups (n = 10 per group): control (corn oil); CCL4 and oral vehicle; CCL4 and Nintedanib at 30 mg/kg/day starting at day 7; CCL4 and Nintedanib 60 mg/kg/day starting at day 7; CCL4 and Nintedanib at 30 mg/kg/day starting at day 14; and CCL4 and Nintedanib 60 mg/kg/day starting at day 14.
Wollin L., Togbe D, & Ryffel B. (2020). Effects of Nintedanib in an Animal Model of Liver Fibrosis. BioMed Research International, 2020, 3867198.
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7

Nintedanib (BIBF 1120) Protocol

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Nintedanib (BIBF 1120) ((methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl) methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate ethane sulfonate salt, batch # 1051764) was provided by Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
Hostettler K.E., Zhong J., Papakonstantinou E., Karakiulakis G., Tamm M., Seidel P., Sun Q., Mandal J., Lardinois D., Lambers C, & Roth M. (2014). Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respiratory Research, 15(1), 157.
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8

Synthesis and Reagent Procurement

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BI 1015550, roflumilast, and nintedanib were synthesized at the chemical facilities of Boehringer Ingelheim (Biberach, Germany). Human recombinant TGF-β, bFGF and IL-1ß were purchased from R&D Systems, Inc. (Minneapolis, MN, United States). Human PGE2 was obtained from Tocris Bioscience (Bristol, United Kingdom).
Herrmann F.E., Hesslinger C., Wollin L, & Nickolaus P. (2022). BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis. Frontiers in Pharmacology, 13, 838449.
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9

LDAC plus Nintedanib for AML Treatment

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LDAC was applied subcutaneously at 20 mg twice daily on days 1 to 10 in 28-day cycles. Nintedanib or placebo tablets identical in appearance (Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany) were orally applied at 200 mg twice daily on days 1 to 28. Dose reductions to 150 mg or 100 mg Nintedanib/placebo twice daily were allowed. As a general rule, non-hematological grade 3 toxicities should be followed by permanent dose reduction off Nintedanib/placebo, unless effectively controlled with supportive therapy. Specific rules applied for gastrointestinal toxicities and liver enzyme elevations. Patients could continue treatment for up to 6 cycles of LDAC plus Nintedanib/placebo, disease progression or relapse, intolerance, or request of treatment discontinuation by patient or investigator. Patients without disease progression after 6 cycles could enter oral maintenance treatment with Nintedanib/placebo (up to 12 months from start of therapy).
Berdel A.F., Koch R., Gerss J., Hentrich M., Peceny R., Bartscht T., Steffen B., Bischoff M., Spiekermann K., Angenendt L., Mikesch J.H., Kewitz T., Butterfass-Bahloul T., Serve H., Lenz G., Berdel W.E., Krug U, & Schliemann C. (2022). A randomized phase 2 trial of nintedanib and low-dose cytarabine in elderly patients with acute myeloid leukemia ineligible for intensive chemotherapy. Annals of Hematology, 102(1), 63-72.
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10

Chemically-Induced Liver Fibrosis and HCC

Cited 1 time
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We generated a chemically-induced model of HCC and fibrosis in male C57BL/6J mice (Harlan Laboratories, n=58) by a single injection of N-nitrosodiethylamine (DEN) followed by weekly dosing with carbon tetrachloride (CCl4), as previously described25 (link). Once fibrosis was established, mice were randomized to receive vehicle or nintedanib (50 mg/kg, Boehringer Ingelheim). Mice were sacrificed at different time-points and liver and tumor tissue samples were collected and processed for histological, transcriptomic and protein expression analyses (see Supplementary material). All experimental procedures were carried out following the approval of the institutional ethical committee of the University of Barcelona and Hospital Clinic of Barcelona. Additionally, liver samples of a choline-deficient high-fat diet (CD-HFD) fed mouse model reported in a recent study26 (link) were collected. A total of 25 samples were processed for transcriptomic profiling, including mice fed a chow diet (n=5) or CD-HFD for 12 months and given: vehicle (n=4); aspirin/clopidogrel (Asp/Clo) (n=6) or sulindac (n=10).
Moeini A., Torrecilla S., Tovar V., Montironi C., Andreu-Oller C., Peix J., Higuera M., Pfister D., Ramadori P., Pinyol R., Solé M., Heikenwälder M., Friedman S.L., Sia D, & Llovet J.M. (2019). An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents. Gastroenterology, 157(5), 1383-1397.e11.
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