Abstract
Simple SummaryThe combination of Resminostat (HDACi) and Ruxolitinib (JAKi) exerted cytotoxic effects and inhibited proliferation of CTCL cell lines (MyLa, SeAx) in vitro. The aim of the present study was to validate their antitumor effects in vivo using the chick embryo chorioallantoic membrane (CAM) model, which allows quick and efficient monitoring of tumor growth, migration, invasion, and metastatic potential. The drug combination exhibited a significant inhibition of primary tumor size, and inhibited intravasation and extravasation of tumor cells to the liver and lung. It also exerted an inhibitory effect in the migration and invasion of tumor cells and significantly reduced key signaling pathway activation. Our data demonstrate that the CAM assay could be employed as a preclinical in vivo model in CTCL for pharmacological testing, and that the combination of Resminostat and Ruxolitinib exerts significant antitumor effects in CTCL progression that need to be further evaluated in a clinical setting.The combination of Resminostat (HDACi) and Ruxolitinib (JAKi) exerted cytotoxic effects and inhibited proliferation of CTCL cell lines (MyLa, SeAx) in previously published work. A xenograft tumor formation was produced by implanting the MyLa or SeAx cells on top of the chick embryo chorioallantoic membrane (CAM). The CAM assay protocol was developed to monitor the metastatic properties of CTCL cells and the effects of Resminostat and/or Ruxolitinib in vivo. In the spontaneous CAM assays, Resminostat and Ruxolitinib treatment inhibited the cell proliferation (p < 0.001) of MyLa and SeAx, and induced cell apoptosis (p < 0.005, p < 0.001, respectively). Although monotherapies reduced the size of primary tumors in the metastasis CAM assay, the drug combination exhibited a significant inhibition of primary tumor size (p < 0.0001). Furthermore, the combined treatment inhibited the intravasation of MyLa (p < 0.005) and SeAx cells (p < 0.0001) in the organs, as well as their extravasation to the liver (p < 0.0001) and lung (p < 0.0001). The drug combination also exerted a stronger inhibitory effect in migration (p < 0.0001) rather in invasion (p < 0.005) of both MyLa and SeAx cells. It further reduced p-p38, p-ERK, p-AKT, and p-STAT in MyLa cells, while it decreased p-ERK and p-STAT in SeAx cells in CAM tumors. Our data demonstrated that the CAM assay could be employed as a preclinical in vivo model in CTCL for pharmacological testing. In agreement with previous in vitro data, the combination of Resminostat and Ruxolitinib was shown to exert antitumor effects in CTCL in vivo.
Highlights
Cutaneous T-cell Lymphomas (CTCLs) present a diverse group of extra-nodal nonHodgkin lymphomas characterized by clonal growth of malignant T cells in the skin [1]
The most common type of CTCL is Mycosis Fungoides (MF), which is characterized by patches, infiltrated plaques, or tumors [2], whereas Sezary Syndrome (SS) is characterized by erythroderma, lymphadenopathy, and the presence of a malignant T cell clone in the peripheral blood and skin [3,4]
It was shown that monotherapies decreased cell viability and enhanced apoptosis when compared to vehicle control without, reaching statistical significance (Figure 1A,B)
Summary
Cutaneous T-cell Lymphomas (CTCLs) present a diverse group of extra-nodal nonHodgkin lymphomas characterized by clonal growth of malignant T cells in the skin [1]. MF/SS are incurable and generally lethal in advanced stages [5], characterized by a chronic, relapsing course that necessitates repeat treatment regimens [6]. Therapeutic strategies that combine novel agents with current treatment options may prove beneficial in the future management of CTCL patients [7]. To this end, there is a need for better understanding of the major biological mechanisms underlying CTCL to develop more effective treatments and improve patients’ survival [8]
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