Ames E, Hallett W H D, Murphy W J
Department of Microbiology and Immunology, University of Nevada School of Medicine, University of Nevada Reno, Reno, NV 89557, USA.
Clin Exp Immunol. 2009 Mar;155(3):504-13. doi: 10.1111/j.1365-2249.2008.03818.x.
The proteasome inhibitor, bortezomib, has direct anti-tumour effects and has been demonstrated to sensitize tumour cells to tumour necrosis factor-related apoptosis-inducing ligand-mediated apoptosis. Natural killer (NK) cells are effective mediators of anti-tumour responses, both through cytotoxic granule killing and apoptosis-inducing pathways. We therefore investigated if bortezomib sensitized human breast cancer cells to killing by the human NK cell line, NK-92. Bortezomib was unable to sensitize MDA-231 breast cancer cells to NK cell-mediated killing in short-term in vitro assays. However, bortezomib did cause these cells to up-regulate apoptosis-related mRNA as well as death receptors on the cell surface. In a long-term in vitro tumour outgrowth assay that allows NK cells to use their full repertoire of killing pathways, bortezomib sensitized three breast cancer cell lines to NK cell-mediated killing, which led to greater anti-tumour effects than either treatment alone. We then used a xenogeneic mouse model in which CB-17 SCID mice were injected with human breast cancer cells. This model displayed the effectiveness of NK-92 cells, but the addition of bortezomib did not increase the survival further or reduce the number of lung metastases in tumour-bearing mice. However, while bortezomib was highly cytotoxic to NK-92 cells in vitro, bortezomib treatment in vivo did not decrease NK-92 function, suggesting that through alternative dosing or timing of bortezomib, greater efficacy may occur from combined therapy. These data demonstrate that combined treatment of human breast cancer with bortezomib and NK cells has the potential to generate superior anti-tumour responses than either therapy alone.
蛋白酶体抑制剂硼替佐米具有直接的抗肿瘤作用，并且已被证明可使肿瘤细胞对肿瘤坏死因子相关凋亡诱导配体介导的凋亡敏感。自然杀伤（NK）细胞是抗肿瘤反应的有效介质，可通过细胞毒性颗粒杀伤和凋亡诱导途径发挥作用。因此，我们研究了硼替佐米是否能使人类乳腺癌细胞对人NK细胞系NK-92的杀伤敏感。在短期体外试验中，硼替佐米无法使MDA-231乳腺癌细胞对NK细胞介导的杀伤敏感。然而，硼替佐米确实导致这些细胞上调凋亡相关mRNA以及细胞表面的死亡受体。在长期体外肿瘤生长试验中，该试验允许NK细胞充分利用其所有杀伤途径，硼替佐米使三种乳腺癌细胞系对NK细胞介导的杀伤敏感，这导致比单独任何一种治疗都具有更强的抗肿瘤作用。然后，我们使用了一种异种小鼠模型，其中向CB-17 SCID小鼠注射人乳腺癌细胞。该模型显示了NK-92细胞的有效性，但添加硼替佐米并未进一步提高荷瘤小鼠的生存率或减少肺转移瘤的数量。然而，虽然硼替佐米在体外对NK-92细胞具有高度细胞毒性，但体内硼替佐米治疗并未降低NK-92的功能，这表明通过改变硼替佐米的给药方式或给药时间，联合治疗可能会产生更大的疗效。这些数据表明，硼替佐米与NK细胞联合治疗人类乳腺癌有可能产生比单独任何一种治疗都更优越的抗肿瘤反应。
