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. 2013 Apr 15;5(2):430–461. doi: 10.3390/cancers5020430

Figure 1.

Figure 1

HDACi and DNMTi target the MM cell. (A) HDACi and DNMTi activate the intrinsic apoptotic pathway by disrupting the balance of anti- and pro-apoptotic molecules concomitant with the release of cytochrome-c and AIF from mitochondria. HDACi also activate the extrinsic pathway by inducing death-receptor expression. In addition, acetylation (green circle) of Ku70 by HDACi results in degradation of FLIP thereby relieving the inhibition of caspase-8 by FLIP. (B) HDAC and DNMTi induce cell cycle arrest by inducing CDK inhibitors and repressing CDK and cyclin proteins. (C) HDACi leads to hyperacetylated alpha-tubulin. Thereby, the formation of aggresomes is inhibited what leads to attenuation of the UPR. HDACi also induce acetylation of HSP90 resulting in IKK degradation and inhibition of NF-κB. DNMTi also inhibit NF-κB activity. Both pathways form the rationale for combination therapy with bortezomib. (D) DNMTi induce the expression of Wnt-antagonist resulting in abrogation of Wnt-mediated proliferation and migration in advanced stages of MM. (E) HDACi and DNMTi can act as DNA damaging agents by activating ATR/ATM and inducing phosphorylation (purple circle) of Ckh-1, -2, p53 and H2AX. This results in cell cycle arrest and apoptosis. In addition, HDACi can inhibit DNA repair mechanisms.