Abstract
BackgroundDrug resistance is a significant problem in the treatment of ovarian cancer and can be caused by multiple mechanisms. Inhibition of apoptosis by the inhibitor of apoptosis proteins (IAPs) represents one such mechanism, and can be overcome by a mitochondrial protein called second mitochondria-derived activator of caspases (SMAC). We have previously shown that the ligands of sigma-2 receptors effectively induce tumor cell death. Additionally, because sigma-2 receptors are preferentially expressed in tumor cells, their ligands provide an effective mechanism for selective anti-cancer therapy.MethodsIn the current work, we have improved upon the previously described sigma-2 ligand SW43 by conjugating it to a pro-apoptotic small molecule SMAC mimetic SW IV-52, thus generating the novel cancer therapeutic SW IV-134. The new cancer drug was tested for receptor selectivity and tumor cell killing activity in vitro and in vivo.ResultsWe have shown that SW IV-134 retained adequate sigma-2 receptor binding affinity in the context of the conjugate and potently induced cell death in ovarian cancer cells. The cell death induced by SW IV-134 was significantly greater than that observed with either SW43 or SW IV-52 alone and in combination. Furthermore, the intraperitoneal administration of SW IV-134 significantly reduced tumor burden and improved overall survival in a mouse xenograft model of ovarian cancer without causing significant adverse effects to normal tissues. Mechanistically, SW IV-134 induced degradation of cIAP-1 and cIAP-2 leading to NF-қB activation and TNFα-dependent cell death.ConclusionsOur findings suggest that coupling sigma-2 ligands to SMAC peptidomimetics enhances their effectiveness while maintaining the cancer selectivity. This encouraging proof-of-principle preclinical study supports further development of tumor-targeted small peptide mimetics via ligands to the sigma-2 receptor for future clinical applications.
Highlights
Drug resistance is a significant problem in the treatment of ovarian cancer and can be caused by multiple mechanisms
The novel sigma-2/second mitochondria-derived activator of caspases (SMAC) drug conjugate SW IV-134 In continuation of our work on the cancer-selective delivery of drug cargoes via the sigma-2 delivery platform, we extended our efforts from peptides to peptidomimetics
In order to study the mechanism of SW IV-134 mediated cancer cell death, we examined its effect on Inhibitor of apoptosis proteins (IAP) proteins in various ovarian cancer cell lines
Summary
Drug resistance is a significant problem in the treatment of ovarian cancer and can be caused by multiple mechanisms. Inhibition of apoptosis by the inhibitor of apoptosis proteins (IAPs) represents one such mechanism, and can be overcome by a mitochondrial protein called second mitochondria-derived activator of caspases (SMAC). Because sigma-2 receptors are preferentially expressed in tumor cells, their ligands provide an effective mechanism for selective anti-cancer therapy. The disease eventually recurs in a large number of patients leading to death mainly due to the lack of effective treatments against drug resistant disease [3]. Inhibition of apoptosis can prevent cancer cell death and promote the development of drug resistance in various malignancies [5]. The anti-apoptotic activity of IAPs can be overcome by second mitochondria-derived activator of caspases (SMAC), a mitochondrial protein which is released into the cytoplasm in response to apoptotic stimuli [7]. A number of compounds that mimic the function of the SMAC proteins have been described recently with striking pro-apoptotic activity reported in vitro and in vivo [8,9,10,11]
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