p53 Laboratory, Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Cancer Res. 2017 Aug 15;77(16):4342-4354. doi: 10.1158/0008-5472.CAN-17-0424. Epub 2017 Jun 27.
Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a first-line chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed. .
由于骨髓中 p53 意外激活导致的化学毒性仍然是一个未满足的临床挑战。阿霉素是一种一线化疗药物，常导致患者骨髓抑制，从而限制了其疗效。在这项研究中，我们发现 C646，一种可逆的 p300 抑制剂，可下调 p53 转录并选择性地保护非癌细胞免受 p53 依赖性细胞凋亡。C646 处理阻止了调节 p53 活性的特定赖氨酸残基的乙酰化。利用人造血细胞和结直肠癌细胞之间 p53 遗传背景的差异，C646 与阿霉素联合治疗提高了阿霉素的治疗指数。在患有 p53 突变肿瘤的小鼠中给予 C646 可保护它们免受阿霉素引起的中性粒细胞减少和贫血，同时保持抗肿瘤疗效。我们推断，在癌症患者中，特别是在 p53 突变肿瘤患者中，暂时和可逆的 p53 乙酰化抑制可能会保护他们免受严重的化学毒性，同时允许治疗方案有效地进行。
