Beclin 1, the mammalian ortholog of yeast Atg6/Vps30, is part of a Class III PI3K complex that

participates in autophagosome formation, mediating the localization of other autophagy proteins to the pre-autophagosomal membrane [54]. It was first identified in a yeast two-hybrid screen as a Bcl-2-interacting protein [55]. Beclin 1 possesses a BH3 domain that dictates its interaction with the BH3 receptor domain of anti-apoptotic proteins of the Bcl-2 family. Association of Beclin 1 with Bcl-2 family proteins blocks the autophagy-promoting function of Beclin 1 [56]. It has been reported that Beclin 1 directly interacts with Bcl-2, Bcl-xL, Bcl-w and to a lesser extent with Mcl-1 [57]. Overexpression of Bcl-2 or Bcl-xL

has been trans-isomer research buy shown to inhibit autophagy by sequestering Beclin 1 [58]. Accordingly, increased expression buy Ipilimumab or stabilization of BH3-only proteins (such as Bid, Bad or Bik), which bind to anti-apoptotic proteins through their BH3 domain, reduces the availability of anti-apoptotic proteins, thereby disinhibiting Beclin 1-dependent autophagy [56], [57] and [59]. Of note, emerging evidences reveal that the competitive displacement of Beclin 1 by pro-apoptotic proteins may not be of significance at all in turning on autophagy, for only the endoplasmic reticulum (ER)-targeted but not the mitochondrion-targeted Bcl-2 has been shown to inhibit autophagy [39]. For instance, studies have shown that Bcl-2 targeted to the ER but not mitochondrial outer membrane inhibits starvation-induced autophagy [58]. This suggests that binding of Bcl-2 to Beclin 1 prevents it from assembling the pre-autophagosomal vesicles at an ER-associated location. BH3 mimetics are small molecules that have close structural or functional similarity to BH3-only proteins. Most BH3 mimetics that are currently under preclinical and clinical development bind to and antagonize anti-apoptotic members of the Bcl-2 family of proteins [60]. Several excellent reviews on the apoptosis-promoting

effects of these BH3 mimetics have recently been published [51], [61], [62], [63] and [64]. Here, we review the three BH3 mimetics (obatoclax, (−)-gossypol, else and ABT-263) that have advanced furthest clinically in relation to autophagy in a variety of cancers including gastrointestinal cancers. Obatoclax (GX15-070) is a novel BH3 mimetic pan Bcl-2 inhibitor [65]. In vitro, obatoclax binds to all anti-apoptotic Bcl-2 family members and by fluorescence polarization assays has IC50s in the 1–7 μM range for Bcl-2, Bcl-xL, Bcl-w and Mcl-1 [66]. Given the inhibitory effect of anti-apoptotic Bcl-2 family proteins on Beclin 1, obatoclax is proposed to induce autophagy by disrupting anti-apoptotic Bcl-2 family proteins and Beclin 1 interactions.