Targeting Apoptosis-Resistant Proliferation: Imatinib-Based Combinations Induce Durable Cytostatic Arrest in 3D...

Background/Objectives: Endometrial cancer frequently develops resistance to apoptosis-based therapies, highlighting the need for alternative strategies that control tumor growth independently of cell death induction. Three-dimensional (3D) tumor models more accurately recapitulate tumor architecture, cellular interactions, and treatment resistance compared to conventional two-dimensional (2D) cultures. This study aimed to investigate whether imatinib-based combination treatments can enforce sustained cytostatic responses in a 3D endometrial cancer model. Methods: Ishikawa spheroids were treated with imatinib alone or in combination with lithium chloride or medroxyprogesterone acetate. Proliferation was assessed by bromodeoxyuridine incorporation, cell cycle distribution by flow cytometry, and apoptosis by Annexin V/propidium iodide staining over 96 h. Results: Imatinib monotherapy produced modest antiproliferative effects, whereas combination treatments resulted in sustained suppression of DNA synthesis, increased G₀/G₁ accumulation, and reduced S-phase entry. Despite strong growth inhibition, apoptotic fractions remained low across all groups. Conclusions: Imatinib-based combinations suppress 3D endometrial cancer growth predominantly through sustained cell cycle arrest rather than apoptosis induction. Targeting apoptosis-resistant proliferation through cytostatic mechanisms may represent a complementary therapeutic strategy for hormone-responsive endometrial cancer and warrants further translational evaluation.