Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs)

Abstract

Inhibitors of apoptosis (IAPs) are a family of proteins that play a significant role in the control of programmed cell death (PCD). PCD is essential to maintain healthy cell turnover within tissue but also to fight disease or infection. Uninhibited, IAPs can suppress apoptosis and promote cell cycle progression. Therefore, it is unsurprising that cancer cells demonstrate significantly elevated expression levels of IAPs, resulting in improved cell survival, enhanced tumor growth and subsequent metastasis. Therapies to target IAPs in cancer has garnered substantial scientific interest and as resistance to anti-cancer agents becomes more prevalent, targeting IAPs has become an increasingly attractive strategy to re-sensitize cancer cells to chemotherapies, antibody based-therapies and TRAIL therapy. Antagonism strategies to modulate the actions of XIAP, cIAP1/2 and survivin are the central focus of current research and this review highlights advances within this field with particular emphasis upon the development and specificity of second mitochondria-derived activator of caspase (SMAC) mimetics (synthetic analogs of endogenously expressed inhibitors of IAPs SMAC/DIABLO). While we highlight the potential of SMAC mimetics as effective single agent or combinatory therapies to treat cancer we also discuss the likely clinical implications of resistance to SMAC mimetic therapy, occasionally observed in cancer cell lines.

Keywords: Chemotherapy resistance; Combination therapy; Extrinsic apoptotic pathway; Inhibitors of apoptosis proteins; Intrinsic apoptotic pathway.

Fig. 1

Schematic illustration of the extrinsic and intrinsic apoptotic pathways, as well as the inhibitory effect of various IAPs on pro-apoptotic molecules. Extrinsic apoptotic pathway initiated by binding of death ligands, such as FasL or tumor necrosis factor (TNF) to death receptors located on the plasma membrane. This reaction is followed by the recruitment and binding of molecules like Fas-associated death domain protein (FADD) or tumor necrosis factor receptor type 1-associated death domain protein (TRADD) to the cytosolic domain of death receptors. Death-inducing signaling complex (DISC) is formed by death receptor, FADD and caspase 8. DISC formation initiates the signal transduction that culminates in apoptosis via caspase 3/7 activation. Active caspases can enhance apoptosis via cleavage of Bid to tBid; a cross-talk facilitator that mediates the mitochondrial amplification loop. The truncated Bid (t-Bid) promotes the release of cytochrome c, via Bax, in mitochondria. The intrinsic pathway, is initiated within at the outer mitochondrial membrane (OMM) in response to cellular stress. As a result, these mediate mitochondrial permeability via interaction ‘pro-apoptotic’ Bcl-2 proteins to stimulate release of cytochrome c and SMAC, which bind and inhibit IAPs. Cytochrome c, Apaf-1 and ATP binds to pro caspase 9 leading to apoptosome formation and activation of caspase 9, which in turn activate caspase 3 permitting the cell to proceed to apoptosis. IAPs are endogenous inhibitors of apoptosis identified in humans. The family members XIAP, cIAP1, cIAP2, NAIP, Livin and Survivin and BRUCE can bind caspases to block apoptosis. Importantly, their dysregulated expression is associated with cancer and chemoresistance

Fig. 2

Downstream apoptotic pathways decide cell fate. In physiological conditions, IAPs mediate cell and tissue homeostasis by mediating apoptosis. a In normal conditions, caspases are uninhibited and the cell under goes apoptosis and b In cancer pathology, the cell escapes apoptosis and proceeds to tumor formation. IAPs are endogenous proteins that inactivate caspases via direct binding, preventing apoptosis thus contributing to oncogenesis and resistance to therapy. c Strategies to target IAPs for anti-cancer therapy include RNA knockdown, small molecule inhibitors and SMAC mimetics. SMAC mimetics are listed by their affinity for either XIAP or cIAP1/2 (RED). Also highlighted are various pro-apoptotic factors, often used as parameters, and targets, of successful combinatory therapies that promote apoptosis