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Updated: Mar 6, 2026
Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model
Agata Szymiczek1, Sandra Pastorino2, David Larson1
1Thoracic Oncology Program, University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA.
Background:
Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet.
Methods:
Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)-a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo.
Results:
We show that FTY720 significantly suppressed MM cell viability and anchorage-independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity.
Conclusions:
Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment.
Insights
FTY720, an immunosuppressant, effectively reduced malignant mesothelioma (MM) tumor growth in preclinical models by targeting phosphatase protein 2A (PP2A). This novel therapeutic approach shows promise for MM treatment with minimal toxicity.
Area of Science:
- Oncology
- Cancer Therapeutics
- Immunology
Background:
- Malignant mesothelioma (MM) is an aggressive cancer with poor prognosis and resistance to chemotherapy.
- New therapeutic strategies are urgently needed for MM treatment.
- FTY720, an established immunosuppressant, has demonstrated anti-tumor activity in various cancers.
Purpose of the Study:
- To evaluate the therapeutic potential of FTY720 in malignant mesothelioma (MM).
- To assess the in vitro and in vivo anti-tumor efficacy and mechanism of action of FTY720 in MM.
Main Methods:
- In vitro assessment of FTY720 on MM cell viability and anchorage-independent growth.
- Evaluation of FTY720's mechanism of action involving phosphatase protein 2A (PP2A) and SET protein.
- In vivo studies using a syngeneic mouse model to determine anti-tumor efficacy and toxicity.
Main Results:
- FTY720 significantly inhibited MM cell viability and growth without affecting normal cells.
- FTY720 modulated PP2A activity by displacing the overexpressed SET protein in MM cells.
- FTY720 induced programmed cell death through AKT dephosphorylation and Bcl-2 degradation, with caspase activation and mitochondrial pathway involvement.
- In vivo administration of FTY720 reduced tumor burden in mice with no observed toxicity.
Conclusions:
- FTY720 demonstrates significant anti-tumor activity against malignant mesothelioma in preclinical settings.
- FTY720's mechanism involves targeting the PP2A/SET pathway and inducing apoptosis.
- FTY720 represents a promising therapeutic candidate for MM treatment.
