Study Of The Effects Of Small Molecule Compounds 11(13)-dehydroivaxillin And Adenanthin On Hematological Malignancies

Hematological malignancies are widely defined as a group of cancers of lymphoid and hematopoietic tissues,including Hodgkin's lymphoma,non-Hodgkin's lymphoma,multiple myeloma,acute and chronic leukemia and myelodysplastic syndromes.Non-Hodgkin's lymphoma and multiple myeloma are the two most common diseases in hematological malignancies.Non-Hodgkin's lymphoma is a group of heterogeneous diseases,the highest incidence of hematological malignancies and in the incidence of all tumors ranked seventh.multiple myeloma is a malignant plasma cell disease,originated in the bone marrow of the plasma cells and the incidence rate come in the second place in hematological malignancies.NF-?B signaling pathway is involved in the process of cell survival,cell development,cell proliferation and cell apoptosis,and plays an important role in the development of inflammation,tumor and immune diseases.NF-?B signaling pathway is aberrantly active in non-Hodgkin's lymphoma and multiple myeloma and is closely related to the malignancy and prognosis of these two cancers.Despite great advancements in the treatment of Non-Hodgkin Lymphoma(NHL),sensitivity of different subtypes to therapy varies.Targeting the aberrant activation NF-?B signaling pathways in lymphoid malignancies is a promising strategy.Here,we report that 11(13)-dehydroivaxillin(DHI),a natural compound isolated from the Carpesium genus,induces growth inhibition and apoptosis of NHL cells.DHI inhibits TNF? induced I?B? degradation,NF-?B nuclear translocation,and expression of NF-?B target genes.Applying the cellular thermal shift assay,we further demonstrated that DHI directly interacts with IKK?/IKK? in NHL cells.Interestingly,DHI treatment also reduced the IKK?/IKK? protein level in NHL cells.Consistent with this finding,knockdown of IKK?/IKK? inhibits cell proliferation and enhances DHI-induced proliferation inhibition.Furthermore,DHI treatment significantly inhibits the growth of NHL cell xenografts.In conclusion,we demonstrate that DHI is a novel IKK?/IKK? targeting molecule compound,which may serve as a promising lead compound for anti-NHL therapy.Multiple myeloma is a poorly treated malignant plasma cell disease.NF-?B is aberrantly activated and plays a pivotal role in the survival and proliferation of multiple myeloma cells.Bortezomib achieved a satisfactory effect since applied to clinic therapy as a NF-?B inhibitor,but it is expensive and easily leads to drug resistance and recurrence during the treatment of the patients.Here,we report that adenanthin,a diterpenoid isolated from the leaves of R.adenantha,significantly inhibited the proliferation and induced apoptosis of multiple myeloma cells,moreover,adenanthin targeting the IKK? and inhibiting the NF-?B activation.In conclusion,adenanthin may not only present a promising IKK? inhibitor to anti-multiple myeloma but also provide a novel strategy for the treatment of multiple myeloma.