Valspodar

To investigate the influence of Ku80 inhibition on the chemotherapeutic sensitivity of the T-acute lymphoblastic leukemia(T-ALL) cell line Jurkat, and to explore the potential mechanism.

The transcription and expression level of Ku80 in 6 hematological malignant cell lines were detected by RT-qPCR and Western blot, respectively. The expression of Ku80 in Jurkat cells was detected by Western blot after transfection with the recombinant shKu80 lentiviral vector. The proliferation capacity of Jurkat cells was explored by CCK-8 after Ku80 inhibition. The colony formation ability, apoptosis, and γH2AX(a protein marker of DNA damage) expression in Jurkat cells were investigated after Ku80 silencing and co-treated with etoposide(VP16) for 4 hours through soft agar assay, flow cytometry and Western blot, respectively.

The mRNA level and protein expression of Ku80 were both highest in Jurkat among 6 hematological malignant cell lines. Ku80 expression was successfully down regulated in Jurkat cells after relative plasmid transfected. The proliferative ability of cells was significantly decreased after Ku80 inhibition(P < 0.05). The colony formation capacity of Jurkat cells was obviously reduced and the cells apoptosis and γH2AX expression were increased after Ku80 inhibition, with or without VP16 incubation.

Targeted silencing of Ku80 could enhance the sensitivity of VP16 in Jurkat cells, which might be associated with the elevated level of DNA damage accumulation.

Hemophagocytic lymphohistiocytosis (HLH) is a common and highly fatal hyperinflammatory syndrome characterized by the aberrant activation of macrophages. To date, there is a lack of targeted therapies for HLH. It is validated that macrophages in HLH efficiently phagocytose anti‐CD41‐platelets (anti‐CD41‐PLTs) from immune thrombocytopenia (ITP) patients in previous research. Hence, the pathological mechanisms of ITP are mimicked and anti‐CD41‐PLTs are utilized to load the macrophage‐toxic drug VP16 to construct macrophage‐targetable engineered platelets anti‐CD41‐PLT‐VP16, which is a novel targeted therapy against HLH. Both in vitro and in vivo studies demonstrate that anti‐CD41‐PLT‐VP16 has excellent targeting and pro‐macrophage apoptotic effects. In HLH model mice, anti‐CD41‐PLT‐VP16 prevents hemophagocytosis and inhibits the cytokine storm. Mechanistic studies reveal that anti‐CD41‐PLT‐VP16 increases the cytotoxicity of VP16, facilitating precise intervention in macrophages. Furthermore, it operates as a strategic “besieger” in diminishing hyperinflammation syndrome, which can indirectly prevent the abnormal activation of T cells and NK cells and reduce the Ab‐dependent cell‐mediated cytotoxicity effect. The first platelet‐based clinical trial is ongoing. The results show that after treatment with anti‐CD41‐PLT‐VP16, HLH patients have a threefold increase in the overall response rate compared to patients receiving conventional chemotherapy. In conclusion, anti‐CD41‐PLT‐VP16 provides a general insight into hyperinflammation syndrome and offers a novel clinical therapeutic strategy for HLH.