MTI-101 (cyclized HYD1) binds a CD44 containing complex and induces necrotic cell death in multiple myeloma.
MTI-101 (cyclized HYD1) binds a CD44 containing complex and induces necrotic cell death in multiple myeloma.
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DOI：
10.1158/1535-7163.mct-13-0310
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发表时间：
2013-11
影响因子：
5.7
通讯作者：
Hazlehurst LA
中科院分区：
文献类型：
--
作者：
Gebhard AW;Jain P;Nair RR;Emmons MF;Argilagos RF;Koomen JM;McLaughlin ML;Hazlehurst LA
我们的实验室最近报道，用含有d-氨基酸的肽HYD 1处理诱导多发性骨髓瘤（MM）细胞系的坏死性细胞死亡。由于HYD 1的有趣的生物活性和有前景的体内活性，我们寻求增加线性肽的治疗功效的策略。这些努力导致环化肽模拟物MTI-101，其具有增加的体外活性和作为单一药剂的稳健的体内活性，使用考虑骨髓微环境的两种骨髓瘤模型。MTI-101处理类似于HYD 1诱导活性氧，耗尽ATP水平，并未能激活半胱天冬酶3。此外，MTI-101在选择用于获得对HYD 1的抗性的H929细胞中具有交叉抗性。在这里，我们采用生物素化肽亲和纯化和LC-MS/MS分析的无偏倚化学生物学方法来鉴定MTI-101的结合伴侣。使用这种方法，CD 44被鉴定为主要的结合伴侣。降低CD 44的表达足以诱导MM细胞系中的细胞死亡，表明MM细胞需要CD 44表达才能存活。CD 44 s的异位表达与FAM结合肽的结合增加相关。然而，CD 44 s的异位表达不足以增加对MTI-101诱导的细胞死亡的敏感性。从机制上讲，我们表明MTI-101诱导的细胞死亡通过Rip 1，Rip 3或Drp 1依赖和独立的途径发生。最后，我们表明MTI-101作为单一药剂在SCID-Hu骨植入物和5 TGM 1多发性骨髓瘤体内模型中具有稳健的活性。
Our laboratory recently reported that treatment with the d-amino acid containing peptide HYD1 induces necrotic cell death in multiple myeloma (MM) cell lines. Due to the intriguing biological activity and promising in vivo activity of HYD1, we pursued strategies for increasing the therapeutic efficacy of the linear peptide. These efforts led to a cyclized peptidomimetic, MTI-101, with increased in vitro activity and robust in vivo activity as single agent using two myeloma models that consider the bone marrow microenvironment. MTI-101 treatment similar to HYD1 induced reactive oxygen species, depleted ATP levels and failed to activate caspase 3. Moreover, MTI-101 is cross-resistant in H929 cells selected for acquired resistance to HYD1. Here, we pursued an unbiased chemical biology approach using biotinylated peptide affinity purification and LC-MS/MS analysis to identify binding partners of MTI-101. Using this approach CD44 was identified as a predominant binding partner. Reducing the expression of CD44 was sufficient to induce cell death in MM cell lines, indicating that MM cells require CD44 expression for survival. Ectopic expression of CD44s correlated with increased binding of the FAM-conjugated peptide. However ectopic expression of CD44s was not sufficient to increase the sensitivity to MTI-101 induced cell death. Mechanistically, we show that MTI-101 induced cell death occurs via a Rip1, Rip3 or Drp1 dependent and independent pathway. Finally, we show that MTI-101 has robust activity as a single agent in the SCID-Hu bone implant and 5TGM1 in vivo model of multiple myeloma.