Research Article: Apoptosis Induction and Gene Expression Profile Alterations of Cutaneous T-Cell Lymphoma Cells following Their Exposure to Bortezomib and Methotrexate

Date Published: January 20, 2017

Publisher: Public Library of Science

Author(s): Vassiliki Mpakou, Evangelia Papadavid, Frieda Kontsioti, Eugene Konsta, Miriam Vikentiou, Aris Spathis, Sotiris Papageorgiou, Diamantina Vasilatou, Konstantinos Gkontopoulos, Efthimia Mpazani, Petros Karakitsos, Dimitrios Rigopoulos, George Dimitriadis, Vasiliki Pappa, Peiwen Fei.


Mycosis fungoides (MF) and its leukemic variant Sézary syndrome (SS) comprise the majority of CTCL, a heterogenous group of non-Hodgkins lymphomas involving the skin. The CTCL’s resistance to chemotherapy and the lack of full understanding of their pathogenesis request further investigation. With the view of a more targeted therapy, we evaluated in vitro the effectiveness of bortezomib and methotrexate, as well as their combination in CTCL cell lines, regarding apoptosis induction. Our data are of clinical value and indicate that the bortezomib/methotrexate combinational therapy has an inferior impact on the apoptosis of CTCL compared to monotherapy, with bortezomib presenting as the most efficient treatment option for SS and methotrexate for MF. Using PCR arrays technology, we also investigated the alterations in the expression profile of genes related to DNA repair pathways in CTCL cell lines after treatment with bortezomib or methotrexate. We found that both agents, but mostly bortezomib, significantly deregulate a large number of genes in SS and MF cell lines, suggesting another pathway through which these agents could induce apoptosis in CTCL. Finally, we show that SS and MF respond differently to treatment, verifying their distinct nature and further emphasizing the need for discrete treatment approaches.

Partial Text

Cutaneous T-cell lymphomas (CTCLs) are rare skin malignancies, comprising a heterogeneous group of non-Hodgkin lymphomas derived from skin-homing mature T-cells [1]. Mycosis fungoides (MF) and Sézary syndrome (SS) are considered as the commonest CTCL types and together account for approximately 50% of all CTCL cases [2, 3]. MF is considered as the commonest type of CTCL and is initially characterized by patches and infiltrated plaques on the skin which eventually evolve into tumors [4, 5]. SS is the leukemic variant of MF and is characterized by erythroderma, lymphadenopathy and the presence of a malignant T-cell clone in the peripheral blood and the skin [2, 5].

Although many chemotherapeutic agents have been used in the treatment of MF/SS, no single therapy has shown superior or efficient effect in the long term, especially for refractory, extensive and/or advanced disease, which are mostly approached through systemic treatments that also fail to provide a permanent therapeutic solution [33]. Since there are no current curative treatment options for CTCL patients, there is an even higher necessity for a better insight into the pathogenesis of the disease.




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