Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents Medicine, University Hospital Frankfurt, Goethe University Frankfurt am Main , Frankfurt , Germany.
Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt am Main , Frankfurt , Germany.
Front Pediatr. 2014 Jul 18;2:75. doi: 10.3389/fped.2014.00075. eCollection 2014.
Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment option for high-risk hematological malignancies, and may also be offered to patients with solid malignancies refractory to conventional therapies. In case of patients' relapse, refractory tumor cells may then be targeted by cellular therapy-based combination strategies. Here, we investigated the potential of small molecule IAP (SMAC mimetic) BV6 in increasing cytokine-induced killer (CIK) cell-mediated cytotoxicity against different tumor targets. Four-hour pre-incubation with 2.5 μMol BV6 moderately enhanced CIK cell-mediated lysis of hematological (H9, THP-1, and Tanoue) and solid malignancies (RH1, RH30, and TE671). However, BV6 also increased apoptosis of non-malignant cells like peripheral blood mononuclear cells and most notably had an inhibitory effect on immune cells potentially limiting their cytotoxic potential. Hence, cytotoxicity increased in a dose-dependent manner when BV6 was removed before CIK cells were added to tumor targets. However, cytotoxic potential was not further increasable by extending BV6 pre-incubation period of target cells from 4 to 12 h. Molecular studies revealed that BV6 sensitization of target cells involved activation of caspases. Here, we provide evidence that SMAC mimetic may sensitize targets cells for CIK cell-induced cell death. However, BV6 also increased apoptosis of non-malignant cells like CIK cells and peripheral mononuclear cells. These findings may therefore be important for cell- and small molecule IAP-based combination therapies of resistant cancers after allogeneic HSCT.
同种异体造血干细胞移植（HSCT）是治疗高危血液病的一种成熟方法，也可能用于对常规治疗耐药的实体恶性肿瘤患者。如果患者复发，耐药的肿瘤细胞可能成为基于细胞疗法的联合策略的靶向目标。在这里，我们研究了小分子 IAP（SMAC 模拟物）BV6 增加细胞因子诱导的杀伤（CIK）细胞对不同肿瘤靶标介导的细胞毒性的潜力。BV6 预处理 4 小时可适度增强 CIK 细胞对血液系统（H9、THP-1 和 Tanoue）和实体恶性肿瘤（RH1、RH30 和 TE671）的杀伤作用。然而，BV6 也增加了外周血单个核细胞等非恶性细胞的凋亡，最值得注意的是，它对免疫细胞有抑制作用，限制了其细胞毒性潜力。因此，当在将 CIK 细胞添加到肿瘤靶标之前去除 BV6 时，细胞毒性呈剂量依赖性增加。然而，通过将靶细胞的 BV6 预孵育时间从 4 小时延长至 12 小时，细胞毒性并没有进一步增加。分子研究表明，BV6 敏化靶细胞涉及半胱天冬酶的激活。在这里，我们提供的证据表明，SMAC 模拟物可能使靶细胞对 CIK 细胞诱导的细胞死亡敏感。然而，BV6 还增加了 CIK 细胞和外周单核细胞等非恶性细胞的凋亡。因此，这些发现对于同种异体 HSCT 后耐药性癌症的基于细胞和小分子 IAP 的联合治疗可能非常重要。
