ADAM17 Inhibition Increases the Impact of Cisplatin Treatment in Ovarian Cancer Spheroids

Nina Hedemann; Andreas Herz; Jan Hendrik Schiepanski; Jan Dittrich; Susanne Sebens; Astrid Dempfle; Julia Feuerborn; Christoph Rogmans; Nils Tribian; Inken Flörkemeier; Jörg Weimer; Sandra Krüger; Nicolai Maass; Dirk O Bauerschlag

doi:10.3390/cancers13092039

ADAM17 Inhibition Increases the Impact of Cisplatin Treatment in Ovarian Cancer Spheroids

Cancers (Basel). 2021 Apr 23;13(9):2039. doi: 10.3390/cancers13092039.

Affiliations

¹ Department of Gynecology and Obstetrics, Kiel University and University Medical Center Schleswig-Holstein Campus Kiel, 24105 Kiel, Germany.
² Institute for Experimental Cancer Research, Kiel University and University Medical Center Schleswig-Holstein Campus Kiel, 24105 Kiel, Germany.
³ Institute of Medical Informatics and Statistics, Kiel University and University Medical Center Schleswig-Holstein Campus Kiel, 24105 Kiel, Germany.
⁴ Department of Pathology, Kiel University and University Medical Center, Schleswig-Holstein Campus Kiel, 24105 Kiel, Germany.

Abstract

Chemotherapy resistance is a major challenge in ovarian cancer (OvCa). Thus, novel treatment combinations are highly warranted. However, many promising drug candidates tested in two-dimensional (2D) cell culture have not proved successful in the clinic. For this reason, we analyzed our drug combination not only in monolayers but also in three-dimensional (3D) tumor spheroids. One potential therapeutic target for OvCa is A disintegrin and metalloprotease 17 (ADAM17). ADAM17 can be activated by chemotherapeutics, which leads to enhanced tumor growth due to concomitant substrate cleavage. Therefore, blocking ADAM17 during chemotherapy may overcome resistance. Here, we tested the effect of the ADAM17 inhibitor GW280264X in combination with cisplatin on ovarian cancer cells in 2D and 3D. In 2D, the effect on five cell lines was analyzed with two readouts. Three of these cell lines formed dense aggregates or spheroids (HEY, SKOV-3, and OVCAR-8) in 3D and the treatment effect was analyzed with a multicontent readout (cytotoxicity, viability, and caspase3/7 activation). We tested the combined therapy on tumor spheroids derived from primary patient cells. In 2D, we found a significant reduction in the half minimal (50%) inhibitory concentration (IC₅₀) value of the combined treatment (GW280264X plus cisplatin) in comparison with cisplatin monotherapy in all five cell lines with both 2D readout assays (viability and caspase activation). In contrast, the combined treatment only showed an IC₅₀ reduction in HEY and OVCAR-8 3D tumor spheroid models using caspase3/7 activity or Celltox^TM Green as the readout. Finally, we found an improved effect of GW280264X with cisplatin in tumor spheroids derived from patient samples. In summary, we demonstrate that ADAM17 inhibition is a promising treatment strategy in ovarian cancer.

Keywords: 3D model; ADAM17; chemotherapy resistance; combined therapy; drug testing; multicontent readout; ovarian cancer; primary cells; primary spheroids; spheroids.