近日，抗肿瘤药物和药理课题组吴少瑜副教授在Oncotarget上发表了题为“Bis-cyclopropane analog of disorazole C1 is a microtubule-destabilizing agent active in ABCB1-overexpressing human colon cancer cells”的研究论文。
该论文研究了用化学方法合成的微生物发酵产物(-)-CP2-disorazole C1对人结肠癌细胞的作用。研究表明，(-)-CP2-disorazole C1对一系列人结肠癌细胞增殖具有抑制作用，特别对长春新碱和泰索帝耐药的结肠癌细胞HCT15和H630R1都具有敏感性。通过对(-)-CP2-disorazole C1作用机制研究发现，此化合物对β型的微管蛋白具有特异性抑制作用，并且通过降低c-Myc, APC, Rb和其他一些关键的蛋白通路，抑制血管生成等方面起到了对人结肠癌细胞的抑制作用。根据以上研究结果表明，(-)-CP2-disorazole C1是一个具有非常大潜力的人结肠癌治疗的候选化合物。
Wu S, Guo Z, Hopkins CD,Wei N, Chu E, Wipf P, Schmitz JC
Bis-cyclopropane analog of disorazole C1 is a microtubule-destabilizing agent active in ABCB1-overexpressing human colon cancer cells. Oncotarget. 2015 Dec 1;6(38):40866-79.
The novel, chemically stabilized disorazole analog, (-)-CP2-disorazole C1 (1) displayed potent anti-proliferative activity against a broad-spectrum of human colorectal cancer cells. HCT15 and H630R1 cell lines expressing high basal levels of the ABCB1 protein, known to cause multi-drug resistance, were also sensitive to growth inhibition by 1 but were resistant to both vincristine and docetaxel, two commonly used microtubule inhibitors. Compound 1 exhibited strong inhibition of tubulin polymerization at a level comparable to vincristine. In addition, treatment with 1 resulted in decreased protein levels of β-tubulin but not α-tubulin. An analysis of cellular proteins known to interact with microtubules showed that 1 caused decreased expression of c-Myc, APC, Rb, and additional key cellular signaling pathways in CRC cells. Treatment with compound 1 also resulted in G2/M cell cycle arrest and induction of apoptosis, but not senescence. Furthermore, endothelial spheroid sprouting assays demonstrated that 1 suppressed angiogenesis and can, therefore, potentially prevent cancer cells from spreading and metastasizing. Taken together, these findings suggest that the microtubule disruptor 1 may be a potential drug candidate for the treatment of mCRC.