三阴性乳腺癌目前缺乏已经获批的靶向治疗。肿瘤抑制蛋白P53的编码基因TP53突变可见于大约80%的三阴性乳腺癌病例。氨硫脲属于抑菌抗结核老药，可以抑制细菌核酸合成，由于不良反应较大，临床不再使用。第三代氨硫脲COTI-2可以高效低毒地将P53突变型重新激活为野生型，从而发挥肿瘤抑制作用。
9月19日，施普林格·自然旗下《乳腺癌研究与治疗》在线发表爱尔兰都柏林大学学院、圣文森特大学医院的研究报告，探讨了将COTI-2用于三阴性乳腺癌的靶向治疗。
该研究对18种乳腺癌细胞株进行了MTT比色法测定，利用P53突变型特异抗体PAb240和P53野生型特异抗体PAb1620进行免疫荧光染色测定P53蛋白质折叠，通过表面等离激元共振确定COTI-2与全长P53和DNA结合部位的亲和力，通过流式细胞技术测定细胞凋亡。
结果，三阴性乳腺癌细胞株与非三阴性乳腺癌细胞株相比，对COTI-2显着有效（P=0.04）。此外，P53突变型与P53野生型细胞相比，半数抑制浓度显着较低（P=0.001）。COTI-2可以与全长P53和突变型P53的DNA结合部位结合。COTI-2可以引起PAb1620染色增加、PAb240染色减少，表明突变蛋白质重新折叠。而且，COTI-2可以诱发三阴性乳腺癌细胞凋亡。
因此，该研究结果表明，COTI-2可以重新激活突变型P53并抑制三阴性乳腺癌细胞生长，利用COTI-2靶向突变型P53可能成为治疗P53突变型三阴性乳腺癌的新方法。
Breast Cancer Res Treat. Sep 19.
COTI-2 reactivates mutant p53 and inhibits growth of triple-negative breast cancer cells.
Naoise C. Synnott, David O"Connell, John Crown, Michael J. Duffy.
University College Dublin, Dublin, Ireland; St. Vincent"s University Hospital, Dublin, Ireland.
PURPOSE: Triple-negative breast cancer (TNBC) currently lacks an approved targeted therapy. The tumour suppressor TP53 gene is mutated in approximately 80% of TNBC cases. COTI-2 is a third-generation thiosemicarbazone engineered for high efficacy and low toxicity which acts by reactivating mutant p53 to a WT form. The aim of this study was to investigate COTI-2 as a targeted therapy for TNBC patients.
METHODS: Using a panel of 18 breast cell lines, we carried out MTT assay. p53 protein folding was determined by immunofluorescent staining with the p53 mutant-specific antibody PAb240 and the p53 WT-specific PAb1620. Surface plasmon resonance was used to determine binding affinity of COTI-2 to full length (FL) p53, and the DNA-binding domain (DBD). Flow cytometry was used to measure apoptosis.
RESULTS: TNBC cell lines were significantly more responsive to COTI-2 than non-TNBC cell lines (p=0.04). Furthermore, lower IC50 values were found in p53 mutant compared to p53 WT cells (p=0.001). COTI-2 was shown to bind to FL and DBD of mutant p53. Treatment resulted in an increase in staining with PAb1620 which coincided with a decrease in staining with PAb240, suggesting refolding of the mutant protein. In addition, COTI-2 was found to induce apoptosis in TNBC cell lines.
CONCLUSION: We conclude that targeting mutant p53 with COTI-2 is a potential approach for treating p53-mutated TNBC.
KEYWORDS: p53 TP53 COTI-2 Triple-negative breast cancer Treatment APR-246
DOI: 10.1007/s10549-019-05435-1
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