However, the mechanism by which obatoclax deliberates Beclin 1 from Mcl-1 is unclear. Interestingly, a recent study demonstrates that obatoclax combined with laptatinib increases the protein level of Noxa, which competes away Mcl-1 from Beclin 1 leading to autophagy induction [69]. Till now, there

is rare evidence indicating obatoclax liberates Beclin 1 from its restraint by direct interacting with anti-apoptotic Bcl-2 family proteins. Therefore, http://www.selleckchem.com/products/CAL-101.html the mechanism by which obatoclax deliberates Beclin 1 from its Bcl-2 binding partners appears to be more complicated than expected. Notably, several studies have shown that Beclin 1 independent induction of autophagy by obatoclax, as knockdown of Beclin 1 failed to blunt obatoclax-induced autophagy [70] and [71]. In this regard, inhibition of mTOR signaling pathway by obatoclax may provide an alternative mechanism for autophagy induction [67] and [69]. Although obatoclax has been shown to engage autophagy in various cancer cells (Table 2), the critical question whether or not obatoclax-stimulated autophagic activity promotes or inhibits cell death has been controversially discussed. On one hand, obatoclax-induced autophagy has been linked to cell death, as genetic or pharmacological blockage of autophagy was found to inhibit cell death [67], [68], [70], [72], [73], [74], [75], [76] and [77]. On the other hand, inhibition Alisertib in vitro of autophagy was demonstrated to enhance obatoclax-induced

cell death, supporting a pro-survival function of autophagy [78]. Interestingly, obatoclax-induced autophagy also appears to act as a bystander, as blockade of autophagy

by silencing Atg7 does not impair obatoclax-triggered cytotoxicity [71]. Besides the above controversial points on the functional relevance of autophagy for obatoclax-induced cytotoxicity, the molecular mechanisms Sodium butyrate that link autophagy to cell death upon treatment with obatoclax is in exploration up till now. In this scenario, subcytotoxic dose of obatoclax (100 nM) combined with dexamethasone has been shown to activate autophagy-dependent necroptosis, which bypassed the block in mitochondrial apoptosis. Execution of cell death was strictly dependent on expression of receptor-interacting protein (RIP-1) kinase, a key regulator of necroptosis [77]. However, it was unclear how RIP-1 was activated and how the autophagic machinery was connected to the necroptotic pathway. It is noteworthy that a very recent study seems to have addressed these questions. In this study, obatoclax (200 nM) has been shown to stimulate assembly of the necrosome on autophagosomal membranes, which functions as a key event connecting the induction of autophagy to cell death via necroptosis. Obtoclax promotes the interaction of Atg5, a component of autophagosomal membranes, with key constituents of the necrosome, that is, FADD, RIP1 and RIP3. This leads to the formation of a cytosolic cell death signaling complex that initiates necroptotic cell death [72].