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

Abstract

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.

Pre‐clinical evaluation of proteasome inhibitors for canine and human osteosarcoma

“…Proteasome inhibition has been reported to trigger a multitude of molecular and cellular changes . One of the most common outcomes, which has been reported in many different cell types, is cell cycle arrest.…”

“…D17 was the most sensitive cell line, yet these cells were the slowest to succumb to apoptosis Proteasome inhibition has been reported to trigger a multitude of molecular and cellular changes. 44,45 One of the most common outcomes, which has been reported in many different cell types, 46 If proteasome inhibitors are ultimately employed clinically to treat canine osteosarcoma patients, they may be added to current regimens, which typically involve administration of carboplatin and/or doxorubicin. To gain some insight into the possible interactions between these drugs, OSCA40 cells were co-treated with various concentrations of bortezomib and/or either carboplatin or doxorubicin.…”

Cell signaling in cutaneous T‐cell lymphoma microenvironment: promising targets for molecular‐specific treatment

“…70 Surprisingly, bortezomib/methotrexate combination 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. 70 These results suggest that bortezomib effect may depend on CTCL type in vitro and have to be confirmed in patients. Bortezomib may enhance efficacy when combined with HDAC inhibitor suberoylanilide hydroxamic acid (SAHA).…”

“…69 In order to investigate if CTCL cells apoptotic resistance could be overcome with combination therapy, Mpakou et al proved the combined effect of bortezomib and methotrexate for inducing apoptosis. 70 Surprisingly, bortezomib/methotrexate combination 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. 70 These results suggest that bortezomib effect may depend on CTCL type in vitro and have to be confirmed in patients.…”

“…Sors et␣al ., 2006 99 ; Zinzani et␣al ., 2007 75 ; Manfè et␣al ., 2012 16 ; Kim et␣al ., 2012 73 ; Ungewickell et␣al ., 2015 15 ; Mpakou et␣al ., 2017 70 …”