Impact of Nintedanib and Anti-Angiogenic Agents on Uveal Melanoma Cell Behavior

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2024 Feb 21

PMID 38381412

Authors

Vera E Pawlik

Svenja R Sonntag

Salvatore Grisanti

Aysegul Tura

Vinodh Kakkassery

Mahdy Ranjbar

Affiliations

Soon will be listed here.

Abstract

Purpose: The purpose of this study was to investigate the direct impact of the combined angiokinase inhibitor nintedanib as well as the anti-angiogenic agents ranibizumab, bevacizumab, and aflibercept on the primary uveal melanoma (UM) cell line Mel270 and liver metastasis UM cell line OMM2.5.

Methods: The metabolic activity, viability, and oxidative stress levels were analyzed by the Thiazolyl Blue Tetrazolium Bromide (MTT), LIVE/DEAD, and reactive oxygen species (ROS) assays. Expression of intracellular VEGF-A165 and VEGF receptor-2 was detected by immunofluorescent staining. The secretion of VEGF-A165 into the cell culture supernatants was evaluated by VEGF-A165 ELISA.

Results: Nintedanib, at a concentration of 1 µg/mL, resulted in a median reduction of metabolic activity (for Mel270 of approximately 38% and for OMM2.5 of 46% compared to the untreated control) without exerting toxicity in either cell line, whereas the other 3 substances did not result in any changes (which also means that none of the 4 substances led to an increased cell death). Moreover, nintedanib (1 µg/mL) induced oxidative stress in the Mel270 by approximately 1.2 to 1.5-fold compared to the untreated control, but not the OMM2.5 cells.

Conclusions: Nintedanib could suppress the growth of UM cells in a concentration-dependent manner. The metastatic UM cell line OMM2.5 was not sensitive to the pro-oxidant activity of nintedanib. This study was the first to investigate nintedanib in the context of UM. We propose further investigation of this substance to elucidate its effects on this tumor entity with the hope of identifying advantageous therapeutic options for future adjuvant tumor therapies.

References

Kersten R, Tse D, Anderson R, Blodi F . The role of orbital exenteration in choroidal melanoma with extrascleral extension. Ophthalmology. 1985; 92(3):436-43. DOI: 10.1016/s0161-6420(85)34019-8. View

Semenza G . HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med. 2002; 8(4 Suppl):S62-7. DOI: 10.1016/s1471-4914(02)02317-1. View

Yang H, Villani R, Wang H, Simpson M, Roberts M, Tang M . The role of cellular reactive oxygen species in cancer chemotherapy. J Exp Clin Cancer Res. 2018; 37(1):266. PMC: 6211502. DOI: 10.1186/s13046-018-0909-x. View

Folkman J . Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg. 1972; 175(3):409-16. PMC: 1355186. DOI: 10.1097/00000658-197203000-00014. View

Virgili G, Gatta G, Ciccolallo L, Capocaccia R, Biggeri A, Crocetti E . Incidence of uveal melanoma in Europe. Ophthalmology. 2007; 114(12):2309-15. DOI: 10.1016/j.ophtha.2007.01.032. View

Ma J, Roelofs K, Russell L, Weis E, Chen S . Rapid growth of primary uveal melanoma following intravitreal bevacizumab injection: a case report and review of the literature. Digit J Ophthalmol. 2021; 26(3):27-30. PMC: 8031910. DOI: 10.5693/djo.02.2020.06.001. View

Rennel E, Waine E, Guan H, Schuler Y, Leenders W, Woolard J . The endogenous anti-angiogenic VEGF isoform, VEGF165b inhibits human tumour growth in mice. Br J Cancer. 2008; 98(7):1250-7. PMC: 2359649. DOI: 10.1038/sj.bjc.6604309. View

Notting I, Missotten G, Sijmons B, Boonman Z, Keunen J, van der Pluijm G . Angiogenic profile of uveal melanoma. Curr Eye Res. 2006; 31(9):775-85. DOI: 10.1080/02713680600865052. View

Neuchrist C, Erovic B, Handisurya A, Steiner G, Rockwell P, Gedlicka C . Vascular endothelial growth factor receptor 2 (VEGFR2) expression in squamous cell carcinomas of the head and neck. Laryngoscope. 2002; 111(10):1834-41. DOI: 10.1097/00005537-200110000-00031. View

10.

Chatterjee S, Heukamp L, Siobal M, Schottle J, Wieczorek C, Peifer M . Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. J Clin Invest. 2013; 123(4):1732-40. PMC: 3613914. DOI: 10.1172/JCI65385. View

11.

Ebos J, Lee C, Cruz-Munoz W, Bjarnason G, Christensen J, Kerbel R . Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009; 15(3):232-9. PMC: 4540346. DOI: 10.1016/j.ccr.2009.01.021. View

12.

Englinger B, Kallus S, Senkiv J, Heilos D, Gabler L, van Schoonhoven S . Intrinsic fluorescence of the clinically approved multikinase inhibitor nintedanib reveals lysosomal sequestration as resistance mechanism in FGFR-driven lung cancer. J Exp Clin Cancer Res. 2017; 36(1):122. PMC: 5590147. DOI: 10.1186/s13046-017-0592-3. View

13.

Ott M, Gogvadze V, Orrenius S, Zhivotovsky B . Mitochondria, oxidative stress and cell death. Apoptosis. 2007; 12(5):913-22. DOI: 10.1007/s10495-007-0756-2. View

14.

Reck M . Nintedanib: examining the development and mechanism of action of a novel triple angiokinase inhibitor. Expert Rev Anticancer Ther. 2015; 15(5):579-94. DOI: 10.1586/14737140.2015.1031218. View

15.

Gorrini C, Harris I, Mak T . Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013; 12(12):931-47. DOI: 10.1038/nrd4002. View

16.

Cao Y, Cao R, Hedlund E . R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med (Berl). 2008; 86(7):785-9. DOI: 10.1007/s00109-008-0337-z. View

17.

Schnichels S, Hagemann U, Januschowski K, Hofmann J, Bartz-Schmidt K, Szurman P . Comparative toxicity and proliferation testing of aflibercept, bevacizumab and ranibizumab on different ocular cells. Br J Ophthalmol. 2013; 97(7):917-23. DOI: 10.1136/bjophthalmol-2013-303130. View

18.

Makitie T, Summanen P, Tarkkanen A, Kivela T . Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci. 2001; 42(7):1414-21. View

19.

Serova M, Tijeras-Raballand A, Dos Santos C, Martinet M, Neuzillet C, Lopez A . Everolimus affects vasculogenic mimicry in renal carcinoma resistant to sunitinib. Oncotarget. 2016; 7(25):38467-86. PMC: 5122404. DOI: 10.18632/oncotarget.9542. View

20.

Koch K, Refaian N, Hos D, Schlereth S, Bosch J, Cursiefen C . Autocrine impact of VEGF-A on uveal melanoma cells. Invest Ophthalmol Vis Sci. 2014; 55(4):2697-704. DOI: 10.1167/iovs.13-13254. View