TY - JOUR
T1 - The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer
AU - Hashim, Yassar M.
AU - Vangveravong, Suwanna
AU - Sankpal, Narendra V.
AU - Binder, Pratibha S.
AU - Liu, Jingxia
AU - Goedegebuure, S. Peter
AU - Mach, Robert H.
AU - Spitzer, Dirk
AU - Hawkins, William G.
N1 - Funding Information:
This work was funded by the National Institute of Health R01 grant (US NIH 5R01CA16376402) (W.G. Hawkins) and the Barnes-Jewish Hospital Auxiliary Cancer Frontier Fund - 3795 (W.G Hawkins and D. Spitzer). Statistical services were provided by the Biostatistics Core at the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO. The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant #P30 CA091842. Toxicology and pathology studies were supported by the Digestive Diseases Research Core Center at Washington University School of Medicine in St. Louis, MO. Salary support for YH was provided by the Washington University Surgical Oncology Training Grant (T32 CA009621).
Publisher Copyright:
© 2016 The Author(s).
PY - 2017/1/17
Y1 - 2017/1/17
N2 - Background: Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV-134 to sensitize pancreatic cancer cells to gemcitabine. Methods: Using the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer. Results: The sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer. Conclusion: We believe that the strong sensitizing capacity of SW IV-134 in combination with clinically relevant doses of gemcitabine represents a promising treatment option that warrants clinical evaluation.
AB - Background: Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV-134 to sensitize pancreatic cancer cells to gemcitabine. Methods: Using the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer. Results: The sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer. Conclusion: We believe that the strong sensitizing capacity of SW IV-134 in combination with clinically relevant doses of gemcitabine represents a promising treatment option that warrants clinical evaluation.
KW - Combination therapy
KW - Gemcitabine
KW - Pancreatic cancer
KW - Sigma-2 receptors
KW - Sigma-2/SMAC drug conjugate
UR - http://www.scopus.com/inward/record.url?scp=85011265923&partnerID=8YFLogxK
U2 - 10.1186/s13046-016-0470-4
DO - 10.1186/s13046-016-0470-4
M3 - Article
C2 - 28095907
AN - SCOPUS:85011265923
SN - 1756-9966
VL - 36
JO - Journal of Experimental and Clinical Cancer Research
JF - Journal of Experimental and Clinical Cancer Research
IS - 1
M1 - 14
ER -