Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
Hematol Oncol. 2022 Dec;40(5):999-1008. doi: 10.1002/hon.3045. Epub 2022 Jul 14.
Mechanisms underlying interactions between a novel, clinically relevant circularized tumor necrosis factor-related apoptosis inducing ligand (TRAIL) agonist, circularly permuted TRAIL (CPT) have been examined in multiple myeloma (MM) cells sensitive or resistant to bortezomib (BTZ). Various MM cell lines for example, U266, including those resistant to bortezomib-resistant U266 cells were exposed to low nanomolar concentrations of bortezomib ± CPT and apoptosis monitored. Circularly permuted TRAIL and bortezomib synergistically induced apoptosis in both BTZ-naïve and -resistant cells. The regimen up-regulated DR4 receptor internalization in MM cells, known to modulate both NF-κB and extrinsic apoptotic pathways. CPT/BTZ disrupted the non-canonical NF-κB pathway, reflected by tumor necrosis factor (TNF) receptor associated factors 3 (TRAF3) up-regulation, NF-κB inducing kinase down-regulation, diminished p52 and p50 processing, and B-cell lymphoma-extra large (BCL-XL) down-regulation, but failed to inactivate the canonical NF-κB pathway, reflected by unchanged or increased expression of phospho-p65. The regimen also sharply increased extrinsic apoptotic pathway activation. Cells exhibiting TRAF3 knock-down, dominant-negative Fas-associated protein with death domain, knock-down of caspase-8, BCL-2/BCL-XL, or exposure to a caspase-9 inhibitor displayed markedly reduced CPT/BTZ sensitivity. Concordant results were observed in bortezomib-resistant cells. The regimen was also active in the presence of stromal cells and was relatively sparing toward normal CD34 hematopoietic cells. Finally, ex vivo results revealed synergism in primary MM primary cells, including those BTZ, and the CPT/BTZ regimen significantly decreased tumor growth in a patient-derived MM xenograft model. These results indicate that the CPT/BTZ regimen acts via the non-canonical NF-κB as well as intrinsic/extrinsic apoptotic pathways to induce cell death in MM cells, and may represent an effective strategy in the setting of bortezomib resistance.
已在对硼替佐米（BTZ）敏感或耐药的多发性骨髓瘤（MM）细胞中研究了新型临床相关环化肿瘤坏死因子相关凋亡诱导配体（TRAIL）激动剂，即环状排列 TRAIL（CPT）与相互作用的潜在机制。例如，各种 MM 细胞系，包括对硼替佐米耐药的 U266 细胞系，都暴露于低纳摩尔浓度的硼替佐米±CPT 下，并监测凋亡。CPT 和硼替佐米协同诱导 BTZ 敏感和耐药细胞凋亡。该方案上调了 DR4 受体内化，这已知可调节 NF-κB 和外在凋亡途径。CPT/BTZ 破坏了非典型 NF-κB 途径，反映在肿瘤坏死因子（TNF）受体相关因子 3（TRAF3）上调、NF-κB 诱导激酶下调、p52 和 p50 加工减少以及 B 细胞淋巴瘤-extra large（BCL-XL）下调，而不能使经典 NF-κB 途径失活，反映为磷酸化 p65 的表达不变或增加。该方案还显著增加了外在凋亡途径的激活。表现出 TRAF3 敲低、具有死亡结构域的 Fas 相关蛋白的显性负性、caspase-8、BCL-2/BCL-XL 敲低或暴露于 caspase-9 抑制剂的细胞对 CPT/BTZ 敏感性明显降低。在硼替佐米耐药细胞中观察到一致的结果。该方案在基质细胞存在下也具有活性，对正常 CD34 造血细胞相对无害。最后，体外结果显示在原代 MM 原代细胞中存在协同作用，包括那些对硼替佐米敏感的细胞，并且 CPT/BTZ 方案显著减少了患者衍生的 MM 异种移植模型中的肿瘤生长。这些结果表明，CPT/BTZ 方案通过非典型 NF-κB 以及内在/外在凋亡途径发挥作用，诱导 MM 细胞死亡，并且在硼替佐米耐药的情况下可能代表一种有效的策略。
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