Use of Enzymatically Activated Carbon Monoxide Donors for Sensitizing Drug-Resistant Tumor Cells.
Federica SodanoBarbara RolandoLoretta LazzaratoCostanzo CostamagnaMariacristina FaillaChiara RigantiKonstantin ChegaevPublished in: International journal of molecular sciences (2023)
The application of gaseous signaling molecules like NO, H 2 S 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 ( 1 ) able to release intracellularly CO and, simultaneously, facilitate fluorescent degradation of products under the action of esterase. The toxicity of 1 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 1 and 1 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.
Keyphrases
- drug resistant
- oxidative stress
- multidrug resistant
- acinetobacter baumannii
- papillary thyroid
- diabetic rats
- ischemia reperfusion injury
- dna damage
- squamous cell
- induced apoptosis
- endothelial cells
- minimally invasive
- gene expression
- radiation therapy
- quantum dots
- locally advanced
- cell death
- nitric oxide
- young adults
- high resolution
- drug induced
- rectal cancer