Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult lymphoma. It is a group of malignant tumors with a large number of clinical manifestations and prognoses. Therefore, it is necessary to explore its unknown potential therapeutic targets. Histone deacetylase inhibitor (HDACi) is a novel drug for the treatment of DLBCL, however pan-HDACis cannot be ignored because of their clinical efficacy. By contrast, specific HDACi is well-tolerated, and LMK-235 is a novel HDACi that is a specific inhibitor of HDAC4 and HDAC5. In this study, we investigated the up-regulation of BCLAF1 through NF-κB signaling pathways in LMK-235, mediating the apoptosis of two diffuse large B-cell lymphoma cell lines, OCI-LY10 and OCI-LY3. Further studies showed that BCLAF1 expression was increased in DLBCL cells after treatment with the NF-κB inhibitor Bay11-7082. The combination of Bay11-7082 and siRNA si-HDAC4 significantly increased BCLAF1 expression and further increased apoptosis. These results indicate that BCLAF1 plays an important role in LMK-235-mediated apoptosis and may be a potential target for the treatment of diffuse large B-cell lymphoma.
Imatinib (IM) resistance has become a critical problem for the treatment of patients with relapsed chronic myeloid leukaemia (CML), so novel therapies are in need. Various isotypes of protein kinases C (PKCs) are up-regulated in CML and related with BCR-ABL regulating several signalling pathways that are crucial to malignant cellular transformation. However, it is still unknown whether PKC isotypes play crucial roles in IM resistance. Therefore, we herein used a PKC pan-inhibitor staurosporine (St). To protect normal cells from damage, a proper dose of St was used, at which IM-resistant CML cells were selectively killed in combination with IM but normal cells survived. The IM resistance of CML cells was best reversed by 4 nM St alone, mainly depending on the G2/M phase arrest. Cell cycle-related proteins p21, CDK2, cyclin A and cyclin B were down-regulated. Meanwhile, PKC-a was more significantly decreased than other PKC isotypes at this concentration. The PKC-a-dependent G2/M phase arrest was induced by down-regulation of CDC23, an important regulator of mitotic progression. Low-dose St also reversed IM resistance in vivo. In conclusion, low-dose St selectively increased the sensitivity of IM-resistant CML to IM by arresting cell cycle in the G2/M phase through PKC-a-dependent CDC23 inhibition.
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