Substance GP-2250 as a new therapeutic agent for malignant peritoneal mesothelioma–a 3D in vitro study

Introduction Malignant peritoneal mesothelioma (MM) is a rare tumor entity. Although cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have increased overall survival, its prognosis is still poor. Established chemotherapeutics include mitomycin C (MMC) and cisplatin (CP), both characterized by severe side effects and poor tolerability. GP-2250 is a novel anti-neoplastic agent, already investigated for its use in pancreatic carcinoma.

Aims This in vitro study aimed to investigate GP-2250 as a treatment option for MM and in combination with cisplatin (CP) and mitomycin C (MMC).

Methods JL-1 and MSTO-211H mesothelioma cell lines were treated with increasing doses of GP-2250, CP and MMC in both monolayer and spheroid (sph.) model. Additionally JL-1 and MSTO-211H spheroids were treated with combination therapies of GP-2250+ CP and+ MMC. Microscopic effects were documented and vital, apoptotic and necrotic cells were measured via flow cytometry. Synergistic and antagonistic effects were analyzed by computing the Combination Index by Chou-Talalay.

Results GP-2250 showed an anti-adhesive effect on JL-1 and MSTO-211H spheroids. It had a dose-dependent cytotoxic effect on both monolayer and spheroid cells, inducing apoptosis and necrosis. Combination treatments with MMC and CP led to significant reductions of the effective doses of MMC and CP as well as additive and synergistic effects.

Conclusion GP-2250 shows promising antineoplastic effects on MM especially in combination with CP and MMC. This forms the basis for further in vivo and clinical investigation in order to broaden treatment options in a highly vulnerable cohort of patients.

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Analysis of cytotoxicity by flow analysis after 48h combination-treatments. The graphs display the share of vital cells of JL-1 sph. and MSTO-211H sph. treated with GP-2250+ CP, Values are means± SD of at least 3 independent experiments with consecutive passages. Asterisk symbols indicate the statistical significance between the combination-treatment and their respective monotherapies.*** p≤ 0.001,** p≤ 0.01, (unpaired t-test). The Combination indices (CI) by Chou-Talalay are marked as follows: CI< 0,9: symbiotic effect+, CI= 0.9 -1.1: additive effect±.

 

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Artikel online veröffentlicht:
19. August 2022