Cucurbitacin I Inhibits Stat3 and Induces Apoptosis in Sézary Cells

• Published in: Journal of investigative dermatology Vol. 128; no. 7; pp. 1691 - 1695
• Main Authors: van Kester, Marloes S., Out-Luiting, Jacoba J., von dem Borne, Peter A., Willemze, Rein, Tensen, Cornelis P., Vermeer, Maarten H.
• Format: Journal Article
• Language: English
• Published: Danvers, MA Elsevier Inc 01.07.2008; Nature Publishing; Elsevier Limited
• Subjects: Apoptosis - drug effects; Biological and medical sciences; Cell Line, Tumor; Dermatology; Dose-Response Relationship, Drug; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Phosphorylation; Sezary Syndrome - drug therapy; Sezary Syndrome - pathology; Skin Neoplasms - drug therapy; Skin Neoplasms - pathology; STAT3 Transcription Factor - antagonists & inhibitors; Triterpenes - pharmacology; Triterpenes - therapeutic use; Skin disease; Sezary cell; Dermatology; Malignant hemopathy; Non Hodgkin lymphoma; Peripheral T cell lymphoma; Chronic; Cutaneous hematologic disease; Sezary syndrome; Cell death; Lymphoproliferative syndrome; Transcription factor STAT3; Inhibitor; Cancer; Apoptosis
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/sj.jid.5701246

Sézary syndrome (Sz) is an aggressive cutaneous CD4+ T-cell lymphoma with tumor cells (Sz cells) localized in the skin, lymph nodes, and peripheral blood. Using western blotting, we demonstrate the expression of phosphorylated (P)-Stat3 in the Sz-derived cell line Seax, and in freshly isolated tumor cells from Sz patients (n=6). In Vitro overnight culture without exogenous cytokines results in decreased expression of P-Stat3 (n=3), indicating that Stat3 is not constitutively activated. Incubation of the Seax cell line with the Jak/Stat3 inhibitor Cucurbitacin I resulted in a time- and concentration-dependent decrease of P-Stat3 and Stat3. In freshly isolated Sz cells (n=3), Cucurbitacin I induced a concentration-dependent decrease in Stat3 expression whereas P-Stat3 was undetectable. Finally, incubation of freshly isolated Sz cells (n=4) with 30μM Cucurbitacin I for 6hours induced apoptosis in the large majority (73–91%) of tumor cells. These data strengthen the notion that activation of Stat3 plays an essential part in the malignant transformation of Sz and provide further rationale for the therapeutical targeting of Stat3 in Sz.