Artemisinin derivatives differently affect cell death of lung cancer subtypes by regulating GPX4 in patient-derived tissue cultures

Resistant tumor cell populations are common after cytostatic drugs treatment. To overcome resistance mechanisms artemisinin derivatives, known for its complementary use during cancer treatement and ferroptosis induction, were investigated both as single agents and in combination with cisplatin (3 µM) in a complex organotypic tissue model of non-small cell lung cancer (NSCLC) patient samples. All substances-artemisinin (ART, 100 µM), artemether (ATM, 50 µM), artesunate (ATS, 20 µM), and dihydroartemisinin (DHA, 10 µM)-showed beneficial effects in most of the investigated patient-derived tissue cultures (PDTC). Tumor proliferation was reduced by DHA and ATS in both, standalone treatment and in combination with cisplatin, surpassing the efficacy of single cisplatin supplementation. In combination with cisplatin tumor apoptosis increased in most of lung squamous cell carcinoma (LUSC) PDTC, but not in lung adenocarcinoma (LUAD). The enzyme GPX4, inhibiting ferroptosis was up-regulated in LUAD but not in LUSC. Taken together, in the complex PDTC model system, LUSC displayed a higher sensitivity to ART derivatives, due to the lack of GPX4-mediated resistance to ferroptosis.