Hashim Yassar M, Vangveravong Suwanna, Sankpal Narendra V, Binder Pratibha S, Liu Jingxia, Goedegebuure S Peter, Mach Robert H, Spitzer Dirk, Hawkins William G
Department of Surgery, Barnes-Jewish Hospital and Washington University School of Medicine St. Louis, 660 S. Euclid Ave, Box 8109, Saint Louis, MO, 63110, USA.
Present Address: Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, 8215-NT, Los Angeles, CA, 90048, USA.
J Exp Clin Cancer Res. 2017 Jan 17;36(1):14. doi: 10.1186/s13046-016-0470-4.
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.
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.
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.
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.
胰腺癌是一种致命的恶性肿瘤，常对传统化疗产生耐药性，这通常与凋亡抑制蛋白（IAPs）的过表达有关。我们最近描述了一种利用sigma-2配体/受体相互作用将第二代线粒体衍生的半胱天冬酶激活剂（SMAC）模拟物选择性递送至癌细胞的新方法。内源性死亡途径激动剂SMAC为对抗IAPs的抗凋亡活性提供了绝佳机会。SMAC模拟物已被用于使多种癌症类型对化疗药物敏感，但尚未考虑癌症选择性递送和适当的细胞定位。在我们目前的研究中，我们测试了sigma-2/SMAC药物偶联物SW IV-134使胰腺癌细胞对吉西他滨敏感的能力。
使用靶向SMAC模拟物SW IV-134，通过药理学方法诱导对X连锁凋亡抑制蛋白（XIAP）的抑制，并单独以及与吉西他滨联合研究其对细胞活力的影响。通过评估半胱天冬酶激活、聚（ADP-核糖）聚合酶（PARP）裂解和膜泡形成（膜联蛋白-V）来进行途径分析，这些是凋亡细胞死亡的关键组成部分。在胰腺癌的临床前小鼠模型中，将单药治疗方案与联合治疗进行比较。
通过使用我们最近设计的靶向SMAC模拟物SW IV-134进行药理学干预，在多种常用的胰腺癌细胞系中，在各单药仅显示最小活性的浓度下，证实了XIAP干扰对吉西他滨的致敏作用。在机制层面，我们确定了凋亡机制的关键组成部分在细胞死亡执行过程中的参与。此外，在胰腺癌的临床前小鼠模型中，联合治疗在减轻肿瘤负担和延长动物寿命方面被证明更具优势。
我们认为，SW IV-134与临床相关剂量的吉西他滨联合使用时的强大致敏能力代表了一种有前景的治疗选择，值得进行临床评估。
