Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10–15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2’s cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.
肿瘤细胞会产生过量的活性氧（ROS），但当这些ROS由外部因素引起时，肿瘤细胞无法有效解毒。一种能在肿瘤细胞内特异性产生毒性水平ROS的制剂，可能成为有效的抗癌药物。CMC-2是一种通过甘氨酸桥将具有生物活性的多酚类姜黄素与二氯乙酸（DCA）偶联而成的分子杂合物。实验检测了CMC-2的细胞毒性抗肿瘤活性，结果显示其对初治型和多药耐药性（MDR）膀胱癌细胞具有同等强度的杀伤效力（<1.0 µM）；CMC-2的效力约为姜黄素或DCA的10-15倍。通过口服灌胃给予小鼠50 mg/kg的CMC-2，可使人体膀胱癌异种移植瘤的生长减少50%以上，且未观察到明显的全身毒性。而使用姜黄素或DCA的剂量仅显示最低限度的抗肿瘤效果。体外实验表明，在同等剂量下，CMC-2对初治型和MDR细胞的毒性依赖于肿瘤细胞内ROS水平的升高，但在正常细胞中未观察到该现象。ROS的升高导致线粒体通透性改变并诱导细胞凋亡。此外，添加羟基自由基清除剂N-乙酰半胱氨酸（NAC）可消除过量ROS的产生并阻断CMC-2的细胞毒性。CMC-2缺乏全身毒性、对化疗敏感及耐药肿瘤具有同等效力，以及具备口服生物利用度等特点，确立了其作为膀胱癌强效药物的潜力。
肿瘤(癌症)患者之家