Substance GP-2250 as a New Therapeutic Agent for Malignant Peritoneal Mesothelioma-A 3-D In Vitro Study

Our plain-English summary of Substance GP-2250 as a New Therapeutic Agent for Malignant Peritoneal Mesothelioma-A 3-D In Vitro Study, by C. Baron, M. Buchholz, B. Majchrzak-Stiller, et al (International Journal of Molecular Sciences, 2022).

The study

• Authors: C. Baron, M. Buchholz, B. Majchrzak-Stiller, I. Peters, D. Fein, T. Müller, W. Uhl, P. Höhn, J. Strotmann, C. Braumann
• Journal: International Journal of Molecular Sciences
• Published: 2022;23(13)
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant peritoneal mesothelioma is a rare tumor entity. Although cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have increased overall survival, its prognosis remains poor. Established chemotherapeutics include mitomycin C (MMC) and cisplatin (CP), both characterized by severe side effects. GP-2250 is a novel antineoplastic agent, currently under clinical investigation. This in vitro study aims to investigate effects of GP-2250 including combinations with CP and MMC on malignant mesothelioma. JL-1 and MSTO-211H mesothelioma cell lines were treated with increasing doses of GP-2250, CP, MMC and combination therapies of GP-2250 + CP/MMC. Microscopic effects were documented, and a flow-cytometric apoptosis/necrosis assay was performed. Synergistic and antagonistic effects were analyzed by computing the combination index by Chou-Talalay. GP-2250 showed an antiadhesive effect on JL-1 and MSTO-211H spheroids. It had a dose-dependent cytotoxic effect on both monolayer and spheroid cultured cells, inducing apoptosis and necrosis. Combination treatments of GP-2250 with MMC and CP led to significant reductions of the effective doses of CP/MMC. Synergistic and additive effects were observed. GP-2250 showed promising antineoplastic effects on malignant mesothelioma cells in vitro especially in combination with CP/MMC. This forms the basis for further in vivo and clinical investigations in order to broaden treatment options.

In plain English

This laboratory study tested an experimental drug, GP-2250, on human mesothelioma cells, alone and combined with cisplatin or mitomycin C, drugs used in heated abdominal chemotherapy. The two commercial cell lines, JL-1 and MSTO-211H, came from men with pleural mesothelioma; JL-1 was described as asbestos associated. Cells were grown as flat layers and as three-dimensional clusters called spheroids. After 48 hours, GP-2250 loosened the spheroids' outer layer and reduced living cells with increasing dose; spheroids were more resistant than flat layers. In spheroids of both lines, some cisplatin plus GP-2250 combinations cut living cells by half or more at lower cisplatin doses than cisplatin alone. Mitomycin C combinations did so only in MSTO-211H: 1000 micromoles per litre of GP-2250 plus 2.5 of mitomycin C cut living cells by 57%, against 5 to 10 needed alone for a 50% cut. In JL-1, the best mitomycin C combination reached 36%, and these combinations worked against each other. Elsewhere, effects ranged from synergy to merely additive to opposing, depending on dose. The authors said cell results cannot be applied directly to patients and called for animal studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-culture study measuring how many cells were killed (cytotoxicity), using flat-layer and three-dimensional spheroid cultures
• Who was studied: Two commercially available human malignant mesothelioma cell lines. MSTO-211H (biphasic) was derived from pleural effusions of a 62-year-old man. JL-1 (epithelioid) was derived from a 54-year-old man with asbestos-associated epithelioid pleural mesothelioma. Work was done at Ruhr-University Bochum, Germany.
• Exposure: 48-hour treatment with increasing doses of GP-2250 alone, cisplatin (CP) alone, mitomycin C (MMC) alone, and combinations of GP-2250 with CP or MMC. No asbestos exposure was studied.
• Main results:
  • Under the microscope, increasing doses of GP-2250 loosened cell-to-cell contacts at the outer edge of the spheroids.
  • In flat-layer (monolayer) cultures, the GP-2250 dose that cut living cells by 50% was computed at 603.7 µmol/L (95% confidence interval 321.21–1134.98) for JL-1 and at 1193.04 µmol/L (95% confidence interval 598.23–2379.26) for MSTO-211H.
  • Cells grown as spheroids were more resistant to GP-2250 than the same cells grown as flat layers.
  • In spheroids, viable cells fell from approximately 70% to 21.03% ± 5.78% in JL-1 at the maximum dose of 1500 µmol/L GP-2250, and to 43.76 ± 6.01% in MSTO-211H at the maximum dose of 2500 µmol/L.
  • In MSTO-211H spheroids, 1000 µmol/L GP-2250 plus 2.5 µmol/L MMC reduced viable cells from 71.6 ± 3.7% (untreated control) to 30.5 ± 1%, equivalent to a 57% reduction (ED57). With 0.5 µmol/L MMC, the same GP-2250 dose gave a 46% reduction (ED46). MMC alone needed 5–10 µmol/L to reach a 50% reduction. The authors described this as lowering the MMC dose for a 50% reduction to 0.5–2.5 µmol/L. Both combinations with 1000 µmol/L GP-2250 were synergistic.
  • In JL-1 spheroids, no GP-2250 plus MMC combination reached a 50% reduction. The strongest, 500 µmol/L GP-2250 plus 5 µmol/L MMC, reduced viable cells from 70.2 ± 3.3% to 44.8 ± 2.9% (ED36). These combinations showed antagonistic rather than synergistic effects.
  • In JL-1 spheroids, GP-2250 plus MMC combinations did not show synergy and were instead antagonistic.
  • In MSTO-211H spheroids, the CP concentration needed to cut viable cells by half or more fell from 20 µmol/L alone to 5–7 µmol/L when combined with 1000 µmol/L GP-2250.
  • In JL-1 spheroids, 500 µmol/L GP-2250 plus 40 µmol/L CP reduced viable cells from 70.2 ± 3.3% to 11.6 ± 4.9%, with a moderate synergistic effect.
  • In JL-1 spheroids, the CP dose needed to cut viable cells by half or more fell from 50 µmol/L alone to 30 µmol/L with 500 µmol/L GP-2250.
  • Overall, both combinations showed synergistic, additive and antagonistic effects, depending on cell line and dose.
• The authors' conclusion: The authors concluded that GP-2250 had anti-adhesive and cytotoxic effects on mesothelioma cells in flat-layer and spheroid cultures, inducing apoptosis and necrosis. They also concluded that combinations with CP and MMC were synergistic or additive and lowered the effective doses. They stated that the study forms a basis for further animal testing and clinical trials.
• Limitations the authors state:
  • Results from cells in the laboratory cannot be applied directly to animal models or patients.
  • The staining method could not tell late apoptotic cells from necrotic cells, which might have produced false positive counts of necrotic cells.
  • The study cannot make general statements about synergy between the drugs.
  • Further studies, especially in animals, are needed to understand the combined effects.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Cytoreductive Surgery, HIPEC, Overall Survival, Prognosis, Mitomycin C, Cisplatin, Mesothelioma.

Related studies

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• Multicenter comprehensive methodological and technical analysis of 832 pressurized intraperitoneal aerosol chemotherapy (PIPAC) interventions performed in 349 patients for peritoneal carcinomatosis treatment: An international survey study — M. Nowacki, M. Alyami, et al. (2018)
• Pharmacokinetics of aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma substance P concentration on chemotherapy-induced nausea and vomiting in Japanese cancer patients — T. Takahashi, Y. Nakamura, et al. (2011)
• In vitro and in vivo therapeutic efficacy of the PPAR-γ agonist troglitazone in combination with cisplatin against malignant pleural mesothelioma cell growth — N. Hamaguchi, H. Hamada, et al. (2010)
• Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma — R. Sciarrillo, A. Wojtuszkiewicz, et al. (2019)
• Current practice in cytoreductive surgery and HIPEC for metastatic peritoneal disease: Spanish multicentric survey — R. Morales-Soriano, N. Esteve-Pérez, et al. (2018)

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