Increased expression of BIRC5/survivin, a crucial regulator of the mitotic spindle checkpoint, is associated with poor prognosis in neuroblastoma (NB), the most common extracranial tumor of childhood. Transcriptional inhibitors of survivin have been tested in adult cancers and inhibitors of survivin homodimerization are emerging. We compared genetic inhibition of survivin transcription with the inhibition of survivin homodimerization by S12 and LQZ-7I, chosen from a larger panel of survivin dimerization inhibitors with activity against NB cells. Mice hemizygous forBirc5were crossed with NB-proneTH-MYCNmice to generateBirc5+/-/MYCNtg/+ mice. The marked decrease of survivin transcription in these mice did not suffice to attenuate the aggressiveness of NB, even when tumors were transplanted into wild-type mice to assure that immune cell function was not compromised by the lack of survivin. In contrast, viability, clonogenicity and anchorage-independent growth of NB cells were markedly decreased by S12. S12 administered systemically to mice with subcutaneous NB xenotransplants decreased intratumoral hemorrhage, albeit not tumor growth. LQZ-7I, which directly targets the survivin dimerization interface, was efficacious in controlling NB cell growth in vitro at markedly lower concentrations compared to S12. LQZ-7I abrogated viability, clonogenicity and anchorage-independent growth, associated with massively distorted mitotic spindle formation. In vivo, LQZ-7I effectively reduced tumor size and cell proliferation of NB cells in CAM assays without apparent toxicity to the developing chick embryo. Collectively, these findings show that inhibiting survivin homodimerization with LQZ-7I holds promise for the treatment of NB and merits further investigation.
BIRC5/survivin作为有丝分裂纺锤体检查点的关键调控因子，其表达增加与儿童最常见的颅外肿瘤——神经母细胞瘤（NB）的不良预后相关。目前已在成人癌症中测试了survivin转录抑制剂，而survivin同源二聚化抑制剂也正在兴起。本研究从具有抗NB细胞活性的survivin二聚化抑制剂库中筛选出S12和LQZ-7I，比较了survivin转录的遗传抑制与survivin同源二聚化抑制的效果。通过将Birc5半合子小鼠与易患NB的TH-MYCN小鼠杂交，获得Birc5+/-/MYCNtg/+基因型小鼠。即使将肿瘤移植至野生型小鼠以确保免疫细胞功能不受survivin缺失影响，这些小鼠体内survivin转录的显著降低仍不足以减弱NB的侵袭性。相比之下，S12能显著降低NB细胞的活力、克隆形成能力和锚定非依赖性生长。对皮下NB异种移植小鼠全身给药S12虽未抑制肿瘤生长，但减少了瘤内出血。直接靶向survivin二聚化界面的LQZ-7I在体外实验中，以显著低于S12的浓度有效控制了NB细胞生长。LQZ-7I通过严重破坏有丝分裂纺锤体形成，完全抑制了细胞活力、克隆形成及锚定非依赖性生长。在鸡胚绒毛尿囊膜实验中，LQZ-7I有效减小了NB肿瘤体积并抑制细胞增殖，且对发育中的鸡胚无明显毒性。综上，这些发现表明LQZ-7I通过抑制survivin同源二聚化在NB治疗中具有应用前景，值得进一步研究。
Inhibition of Survivin Homodimerization Decreases Neuroblastoma Cell Growth
肿瘤(癌症)患者之家