Conjugation to a SMAC mimetic potentiates sigma-2 ligand induced tumor cell death in ovarian cancer

Molecular Cancer

Research

Gunjal Garg¹  Matthew A Powell²  David G Mutch²  Suwanna Vangveravong³  Chenbo Zeng⁴  Robert H Mach⁵  Mary Hornick⁶  Yassar Hashim⁶  Dirk Spitzer⁷  William G Hawkins⁷  Lynne Collins⁸  David Piwnica-Worms⁹ 

[1] Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, 63110, St. Louis, MO, USA;Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, 63110, St. Louis, MO, USA;Siteman Cancer Center, Washington University School of Medicine, 63110, St. Louis, MO, USA;Department of Radiology, Division of Radiological Sciences, Washington University School of Medicine, 63110, St. Louis, MO, USA;Department of Radiology, University of Pennsylvania, Chemistry Building, Room 283, 231 S. 34th St, 19104, Philadelphia, PA, USA;Department of Radiology, University of Pennsylvania, Chemistry Building, Room 283, 231 S. 34th St, 19104, Philadelphia, PA, USA;Britton Chance Professor of Radiology, Director of Radiochemistry, University of Pennsylvania, Chemistry Building, Room 283, 231 S. 34th St, 19104, Philadelphia, PA, USA;Department of Surgery, Washington University School of Medicine, Campus Box 8109, 660 S. Euclid Avenue, 63110, St. Louis, MO, USA;Department of Surgery, Washington University School of Medicine, Campus Box 8109, 660 S. Euclid Avenue, 63110, St. Louis, MO, USA;Siteman Cancer Center, Washington University School of Medicine, 63110, St. Louis, MO, USA;Departments of Cell Biology & Physiology, Developmental Biology, Molecular Imaging Center, Mallinckrodt Institute of Radiology, BRIGHT Institute, 63110, St. Louis, MO, USA;Departments of Cell Biology & Physiology, Developmental Biology, Molecular Imaging Center, Mallinckrodt Institute of Radiology, BRIGHT Institute, 63110, St. Louis, MO, USA;The University of Texas M.D. Anderson Cancer Center, Cancer Systems Imaging Department, Division of Diagnostic Imaging, T. Boone Pickens Academic Tower, 1400 Pressler Street, Unit 1479, 77030, Houston, TX, USA;

关键词: Sigma-2 ligand;    SMAC-peptidomimetic;    Small molecule;    Drug conjugate;    Targeted drug delivery;    Apoptosis;    Ovarian cancer;   

DOI  :  10.1186/1476-4598-13-50

 received in 2013-10-08, accepted in 2014-02-23,  发布年份 2014

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Garg et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.