Functional Depletion of HSP72 by siRNA and Quercetin Enhances Vorinostat-Induced Apoptosis in an HSP72-Overexpressing Cutaneous T-Cell Lymphoma Cell Line, Hut78

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.

Epigenetics: Mechanisms, potential roles, and therapeutic strategies in cancer progression

“…Quercetin also significantly enhanced vorinostat-induced apoptosis and loss of mitochondrial membrane potential. 96 DNMT1, DNMT3b, HDAC1, and HDAC3 have been reported to be highly expressed in choriocarcinoma cancer stem-like cells. Curcumol suppresses their stemness by inhibiting the activities of DNMTs and HDACs.…”

Ageing microenvironment mediates lymphocyte carcinogenesis and lymphoma drug resistance: From mechanisms to clinical therapy (Review)

“…For instance, dasatinib combined with quercetin as a classic senolytic agent is effective in the senescence-associated treatment of solid tumours ( 75 , 139 , 140 ). Dasatinib is a vital tyrosine kinase inhibitor used for targeted leukaemia and lymphoma therapy ( 141 , 142 ). Quercetin, a TCM drug, also exhibits anti-lymphoma effects ( 143 ).…”

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

“…For this reason, a stable HSP70-knockdown CTCL cell line was established, thus confirming the influence of HSP70 reduction on the anti-tumor effects of vorinostat. Subsequently, quercetin was used to reduce HSP70 expression and enhance HDAC activity [ 157 ]. When a proteomic investigation was conducted in 33 lymphoid cell lines to identify novel therapeutic targets for enhancing the effects of HDAC inhibitors, HSP72 showed higher expression in cell lines exhibiting resistance to valproic acid, whose cytotoxic effect was enhanced by the treatment with KNK-437, an inhibitor of HSP72 [ 158 ].…”