Abstract
Histone deacetylase inhibitors (HDACis) are one of the therapeutic options for cutaneous T-cell lymphoma (CTCL), but they have limited effects. We previously demonstrated that HSP72 overexpression is associated with chemoresistance to HDACis in lymphoma cells. The purpose of this study was to investigate whether the functional depletion of HSP72 enhances the effect of the HDACi vorinostat. First, we established a stable HSP72-knockdown CTCL cell line and confirmed the influence of HSP72 reduction on the antitumor effects of vorinostat. Next, we studied the effect of quercetin, an inhibitor of HSP72, on the antineoplastic effects of vorinostat. In five CTCL cell lines examined, HSP72 expression was highest in Hut78 cells, and HSP72 knockdown enhanced vorinostat-induced apoptosis in these cells. Low-dose quercetin reduced HSP72 expression, increased HDAC activity, and enhanced vorinostat-induced suppression of Hut78 cell proliferation. A single low dose of quercetin induced G2 arrest and only slightly increased the sub-G1 cell fraction. Quercetin also significantly enhanced vorinostat-induced apoptosis, caspase-3, caspase-8, and caspase-9 activity, and the loss of mitochondrial membrane potential. HSP72 knockdown enhanced vorinostat-induced apoptosis in an HSP72-overexpressing CTCL cell line, and thus, quercetin may be a suitable candidate for combination therapy with vorinostat in clinical settings.
Highlights
Cutaneous T cell lymphomas (CTCLs) comprise a heterogeneous group of skin-based neoplasms of T-cell origin, with mycosis fungoides (MF) being the most common [1]
We found that high expression of HSP72, a member of the HSP70 family, is positively correlated with histone deacetylase inhibitors (HDACis) resistance in lymphoid cell lines [23,24]
HSP72 mRNA expression was reduced by 40% (Figure 2a), and protein expression was decreased by 20% in knockdown cells (Figure 2b), which were more sensitive to vorinostat than MOCK cells (Figure 2c)
Summary
Cutaneous T cell lymphomas (CTCLs) comprise a heterogeneous group of skin-based neoplasms of T-cell origin, with mycosis fungoides (MF) being the most common [1]. Most patients with early-stage MF follow an indolent course. Management of early-stage MF involves more conservative approaches such as skin-directed therapies. Patients with advanced-stage MF and Sézary Syndrome (SS), a leukemic variant of CTCL, have a poor prognosis with a median survival of less than 5 years [2]. Systemic treatments with biological modulators or targeted therapies are recommended, whereas cytotoxic or immunosuppressive chemotherapies are reserved, as chemotherapy shortens the median time until the treatment in patients with MF/SS [3] and multiagent chemotherapy often induces immunosuppression, which leads to an increased risk of infection [4], one of the most common causes of death in patients with advanced-stage MF/SS [5]. Interferons and histone deacetylase inhibitors (HDACis) afford longer times to the treatment than chemotherapy [6]
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