期刊
MOLECULAR ONCOLOGY
卷 8, 期 5, 页码 956-967出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.molonc.2014.03.005
关键词
Sigma-2 receptor; Smac; IAPs; Pancreas cancer; Selective delivery
类别
资金
- National Institute of Health R01 grant [US NIH 5R01CA16376402, 22-004125-52508]
- Mallinckrodt Institute of Radiology
- NCI Cancer Center Support Grant [P30 CA091842]
- Washington University Surgical Oncology Training Grant [5T32CA00962124]
Pancreatic adenocarcinoma is highly resistant to conventional therapeutics and has been shown to evade apoptosis by deregulation of the X-linked and cellular inhibitors of apoptosis proteins (XIAP and cIAP). Second mitochondria-derived activator of caspases (Smac) induces and amplifies cell death by reversing the anti-apoptotic activity of IAPs. Thus, Smac-derived peptide analogues (peptidomimetics) have been developed and shown to represent promising cancer therapeutics. Sigma-2 receptors are overexpressed in many proliferating tumor cells including pancreatic cancer. Selected ligands to this receptor are rapidly internalized by cancer cells. These characteristics have made the sigma-2 receptor an attractive target for drug delivery because selective delivery to cancer cells has the potential to increase therapeutic efficacy while minimizing toxicity to normal tissues. Here, we describe the initial characterization of SW IV-134, a chemically linked drug conjugate between the sigma-2 ligand SW43 and the Smac mimetic SW IV-52 as a novel treatment option for pancreatic adenocarcinoma. The tumor killing characteristics of our dual-domain therapeutic SW IV-134 was far greater than either component in isolation or in an equimolar mix and suggests enhanced cellular delivery when chemically linked to the sigma-2 ligand. One of the key findings was that SW IV-134 retained target selectivity of the Smac cargo with the involvement of the NF-kappa B/TNF alpha signaling pathway. Importantly,
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