Cucurbitacin E and I target the JAK/STAT pathway and induce apoptosis in Sézary cells

Abstract

Cutaneous T-cell lymphomas and leukemias (CTCLs) are a heterogeneous group of extranodal non-Hodgkin's lymphomas. These are characterized by an accumulation of malignant CD4 + T-lymphocytes in the skin, lymph nodes, and peripheral blood. Novel treatment options are needed for patients who progress to advanced stage disease. Cucurbitacin I has previously shown promising results in Sézary syndrome (Sz). A plethora of cucurbitacins, however, have not yet been tested in CTCL. Herein, we investigated the effect of cucurbitacin E and I in two CTCL cell lines. We show that both cucurbitacins decrease viability and cause apoptosis in these cell lines, although HuT-78 was more affected than SeAx (IC 50 of 17.38 versus 22.01 μM for cucurbitacin E and 13.36 versus 24.47 μM for cucurbitacin I). Moreover, both cucurbitacins decrease viability of primary cells of a Sz patient (56.46% for cucurbitacin E and 59.07% for cucurbitacin I). Furthermore, while JAK2 inhibition leads to decreased viability in SeAx cells (IC 50 of 9.98 and 29.15 μM for AZD1480 and ruxolitinib respectively), both JAK1 and JAK3 do not. This suggests that JAK2 has a preferential role in promoting survival. Western blotting in SeAx cells revealed that both cucurbitacins inhibit STAT3 activation (P < 0.0001), while only cucurbitacin I inhibits STAT5 activation (P = 0.05). This suggests that STAT3 plays a preferential role in the mechanism of action of these cucurbitacins. Nevertheless, a role of STAT5 and JAK2 cannot be excluded and should be explored further. This knowledge could contribute to the development of effective therapies for CTCL and other malignancies involving dysfunction of the JAK/STAT pathway.

Phytochemistry and Cytotoxic Activity of Aquilaria crassna Pericarp on MDA-MB-468 Cell Lines

“…35,36 In recent studies, cucurbitacin E (3) was reported to have an inhibition effect on the phosphorylation process of STAT3. 29,37 Therefore, it would be intriguing to investigate the binding affinity of cucurbitacin E (3), relating to similar cucurbitacins 7−9 and other extracted compounds 1, 2, and 4−6 from A. crassna pericarp with the SH2 domain of STAT3.…”

Cutaneous Lymphocyte Antigen Is a Potential Therapeutic Target in Cutaneous T-Cell Lymphoma

“…In addition, modulation of activation-induced cell death regulators was not observed after HECA-452 treatment of CTCL cells (data not shown). In contrast, anti-CLA antibody induced apoptotic pathways in CLAþ CTCL cells through an in vitro rapid activation (within 30 minutes) of caspases 3/7, 8, and 9 effectors compared with that of other potential or current therapeutic agents such as curbitacin, bexarotene, or cobomarsen (Brouwer et al, 2020;Seto et al, 2018). How HECA-452 exerts its effects did not require complement fixation because it induces cell death in the absence of serum (data not shown) and needs to be clarified.…”

Dietary Glutamine Inclusion Regulates Immune and Antioxidant System, as Well as Programmed Cell Death in Fish to Protect against Flavobacterium columnare Infection

“…Thus it is reasonable that glutamine showed a protective role against apoptosis in fish gill in the present study. In order to further illustrate the regulatory mechanism of glutamine on apoptosis, the genes expression involved in the JAK-STAT signaling pathway were evaluated, which has been identified as one of the principal pathway responsible for apoptosis in mammals [ 92 ]. JAKs including JAK1, JAK2, JAK3, and TYK2, which function as the membrane receptors, can be activated upon preferential ligand binding and then recruits and phosphorylates STATs, preferentially STAT3 and STAT5, on their tyrosine residues [ 93 ].…”