Breast cancer is a major public health problem throughout the world. In this report, we investigated whether CHM-1, a novel synthetic antimitotic agent could be developed into a potent antitumor agent for treating human breast cancer. CHM-1 induced growth inhibition in MDA-MB-231, MDA-MB-453 and MCF-7 cells in a concentration-dependent manner. Importantly, CHM-1 is less toxic to normal breast (HBL-100) cells. CHM-1 interacted with tubulin, markedly inhibited tubulin polymerization, and disrupted microtubule organization. Proteins from control and CHM-1-treated animal tumor specimens were analyzed by two-dimensional electrophoresis and MALDI-TOF mass spectrometry. Our results indicated that CHM-1 increased the expression of SIRT2 protein, an NAD-dependent tubulin deacetylase. A prodrug strategy was also investigated to address the problem of low aqueous solubility and low bioavailability of the antitumor agent CHM-1. The water-soluble prodrug of CHM-1 (CHM-1-P) was synthesized. After oral and intravenous administration, CHM-1-P induced a dose-dependent inhibition of tumor growth. The aforementioned excellent anti-tumor activity profiles of CHM-1 and its prodrug CHM-1-P, suggests that CHM-1-P deserves to further develop as a clinical trial candidate for treating human breast carcinoma.

乳腺癌是全世界主要的公共卫生问题。在这份报告中，我们调查了新型合成抗有丝分裂剂CHM-1是否可以发展为治疗人类乳腺癌的有效抗肿瘤剂。CHM-1以浓度依赖的方式诱导MDA-MB-231，MDA-MB-453和MCF-7细胞的生长抑制。重要的是，CHM-1对正常乳腺（HBL-100）细胞的毒性较小。CHM-1与微管蛋白相互作用，显着抑制微管蛋白聚合，并破坏微管组织。通过二维电泳和MALDI-TOF质谱分析来自对照和CHM-1处理的动物肿瘤标本的蛋白质。我们的结果表明CHM-1增加了SIRT2蛋白（一种NAD依赖性微管蛋白脱乙酰基酶）的表达。还研究了前药策略以解决抗肿瘤剂CHM-1的低水溶性和低生物利用度的问题。合成了CHM-1（CHM-1-P）的水溶性前药。口服和静脉内给药后，CHM-1-P诱导了肿瘤生长的剂量依赖性抑制。CHM-1及其前药CHM-1-P的上述出色的抗肿瘤活性谱表明，CHM-1-P作为治疗人类乳腺癌的临床试验候选者值得进一步发展。