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  • Importantly recent in vivo results demonstrated that combini

    2021-10-22

    Importantly, recent in vivo results demonstrated that combining an HDACi and a IKK inhibitor significantly reduced ovarian tumor growth compared with either inhibitor alone [26]. The slowest tumor growth in the HDACi/IKK inhibition combination group was associated with the lowest CXCL8 tumor and plasma levels, and with the lowest tumor expression of the murine neutrophil (7/4) antigen, indicating a reduced tumor infiltration with mouse neutrophils. Recent studies also demonstrated a key role of the CXC chemokine receptor, CXCR2, in pancreatic cancer development and progression 95, 96. Inhibition of CXCR2 signaling significantly reduced metastases, prolonged survival, and enhanced sensitivity to anti-PD-1 immunotherapy in a mouse model of pancreatic ductal adenocarcinoma [95]. CXCL8-CXCR1/2 signaling has a crucial role in the initiation and progression of solid tumors [46]. Thus, targeting HDACi-induced, IKK-dependent CXCL8 expression may increase the effectiveness of HDACi in treating OC and possibly other solid tumors characterized by increased CXCL8 expression (Figure 3, Key Figure). Targeting IKK activity and NFκB-dependent expression of prosurvival genes induced by HDACi has been investigated in the treatment of hematological malignancies 66, 67, 97, 98. Inhibition of IKK activity and NFκB signaling by Bay 11-7082 or parthenolide potentiated HDACi-mediated cell death in 3ct sale leukemia 3ct sale 66, 97. Inhibition of IKK activity by Bay 11-7082 or the selective IKKβ inhibitor IKK-2 inhibitor IV also augmented the proapoptotic effect of HDACi in multiple myeloma cells [67]. A novel IKKβ inhibitor, LY2409881, exhibited a strong cytotoxic synergistic effect with romidepsin in diffuse large B cell lymphoma (DLBCL) cell lines as well as in vivo, in a DLBCL xenograft model [98]. In addition, the HDACi-induced activation of NFκB in hematological malignancies has served as the basis of many synergistic strategies combining HDACi with proteasome inhibitors that suppress the proteasomal degradation of IκBα [2]. In contrast to hematological malignancies, combination of IKK inhibitors and HDACi has not been considered in the treatment of solid tumors, perhaps because of the limited effectiveness of HDACi in solid cancers as single agents. Many compounds can inhibit IKK activity, including the IKK inhibitors PS1145, BMS345541, SC514, SPC839, ML120B, BAY 11-7082, and the newly developed IKKβ inhibitor LY2409881. In addition, IKK activity can be inhibited by NSAIDs, such as aspirin [89], and by naturally occurring agents, such as curcumin 93, 99, which are pharmacologically safe and have long been used for their chemopreventive and anti-inflammatory properties. Even though IKK inhibitors are not highly potent as single agents, accumulating evidence indicates that they may synergize with HDACi in treating solid cancers 26, 27, 42, 88, 91, 93, 100. The mechanistic basis of this synergy comprises the HDACi-induced and IKK-dependent expression of CXCL8, which increases the survival and proliferation of solid cancer cells. Inhibition of IKK activity suppresses the induced CXCL8 expression, thus potentiating the effectiveness of HDACi in reducing solid tumor growth.
    Concluding Remarks and Future Perspectives Targeting IKK activity and NFκB-dependent transcription induced by HDAC inhibition has been investigated in the treatment of multiple myeloma and other hematological malignancies. In solid tumors, the combination of IKK inhibitors and HDACi has not previously been considered, perhaps because of their limited effectiveness as single agents. Recent data indicate that, by suppressing CXCL8 expression, IKK inhibitors may increase the effectiveness of HDACi in OC and other solid cancers characterized by increased CXCL8 expression (Figure 3). Future studies and clinical trials should examine the effect of IKK-inhibiting agents on increasing the effectiveness of HDACi in OC and other solid cancers characterized by increased CXCL8 expression.