CUDC-101 as a dual-target inhibitor of EGFR and HDAC enhances the anti-myeloma effects of bortezomib by regulating G2/M cell cycle arrest

CUDC-101,an effective and multi-target inhibitor of epidermal growth factor receptor(EGFR),histone deacetylase(HDAC),and human epidermal growth factor receptor 2(HER2),has been reported to inhibit many kinds of cancers,such as acute promyelocytic leukemia and non-Hodgkin's lymphoma.However,no studies have yet investigated whether CUDC-101 is effective against myeloma.Herein,we proved that CUDC-101 effectively inhibits the proliferation of multiple myeloma(MM)cell lines and induces cell apoptosis in a time-and dose-dependent manner.Moreover,CUDC-101 markedly blocked the signaling pathway of EGFR/phosphoinositide-3-kinase(PI3K)and HDAC,and regulated the cell cycle G2/M arrest.Moreover,we revealed through in vivo experiment that CUDC-101 is a potent anti-myeloma drug.Bortezomib is one of the important drugs in MM treatment,and we investigated whether CUDC-101 has a synergistic or additive effect with bortezomib.The results showed that this drug combination had a synergistic anti-myeloma effect by inducing G2/M phase blockade.Collectively,our findings revealed that CUDC-101 could act on its own or in conjunction with bortezomib,which provides insights into exploring new strategies for MM treatment.

Pirh2 mediates the sensitivity of myeloma cells to bortezomib via canonical NF-κB signaling pathway

Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma （MM）. While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 （Pirh2） in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor- kappaB （NF-κB） p65, pp65, plKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of plKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, plKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF- κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.

How are MCPIP1 and cytokines mutually regulated in cancer-related immunity?

Cytokines are secreted by various cell types and act as critical mediators in many physiological processes,including immune response and tumor progression.Cytokines production is precisely and timely regulated by multiple mechanisms at different levels,ranging from transcriptional to post-transcriptional and posttranslational processes.Monocyte chemoattractant protein-1 induced protein 1(MCPIP1),a potent immunosuppressive protein,was first described as a transcription factor in monocytes treated with monocyte chemoattractant protein-1(MCP-1)and subsequently found to possess intrinsic RNase and deubiquitinase activities.MCPIP1 tightly regulates cytokines expression via various functions.Furthermore,cytokines such as interleukin 1 beta(IL-1B)and MCP-1 and inflammatory cytokines inducer lipopolysaccharide(LPS)strongly induce MCPIP1 expression.Mutually regulated MCPIP1 and cytokines form a complicated network in the tumor environment.In this review,we summarize how MCPIP1 and cytokines reciprocally interact and elucidate the effect of the network formed by these components in cancer-related immunity with aim of exploring potential clinical benefits of their mutual regulation.

High levels of serum IL-10 indicate disease progression,extramedullary involvement,and poor prognosis in multiple myeloma

Multiple myeloma(MM)is a common malignant hematological tumor in adults,which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclonal immunoglobulins(M protein),leading to bone destruction,hypercalcemia,anemia,and renal insufficiency(Alexandrakis et al.,2015;Yang et al.,2018).Since a large number of new drugs,represented by proteasome inhibitors and immunomodulators,have been successfullyused to treat MM.