Department of Pharmacy, "Federico II" University of Naples, 80131 Naples, Italy.
Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy.
Int J Mol Sci. 2023 Jul 9;24(14):11258. doi: 10.3390/ijms241411258.
The application of gaseous signaling molecules like NO, HS or CO to overcome the multidrug resistance in cancer treatment has proven to be a viable therapeutic strategy. The development of CO-releasing molecules (CORMs) in a controlled manner and in targeted tissues remains a challenge in medicinal chemistry. In this paper, we describe the design, synthesis and chemical and enzymatic stability of a novel non-metal CORM () able to release intracellularly CO and, simultaneously, facilitate fluorescent degradation of products under the action of esterase. The toxicity of against different human cancer cell lines and their drug-resistant counterparts, as well as the putative mechanism of toxicity were investigated. The drug-resistant cancer cell lines efficiently absorbed and was able to restore their sensitivity vs. chemotherapeutic drugs by causing a CO-dependent mitochondrial oxidative stress that culminated in mitochondrial-dependent apoptosis. These results demonstrate the importance of CORMs in cases where conventional chemotherapy fails and thus open the horizons towards new combinatorial strategies to overcome multidrug resistance.
气态信号分子如 NO、HS 或 CO 的应用被证明是克服癌症治疗中多药耐药性的一种可行的治疗策略。以可控的方式在靶向组织中开发一氧化碳释放分子（CORMs）仍然是药物化学中的一个挑战。在本文中，我们描述了一种新型非金属 CORM（）的设计、合成以及化学和酶稳定性，该 CORM 能够在酯酶作用下释放细胞内 CO，并同时促进荧光产物的降解。研究了对不同人癌细胞系及其耐药对应物的毒性，以及潜在的毒性机制。耐药癌细胞系有效地吸收了，并通过引起 CO 依赖性线粒体氧化应激，最终导致线粒体依赖性细胞凋亡，使它们对化疗药物的敏感性恢复。这些结果表明 CORM 在常规化疗失败的情况下的重要性，从而为克服多药耐药性开辟了新的组合策略的前景。
