Abstract
Colorectal cancer (CRC) is one of the most common malignancies, and multidrug resistance (MDR) severely restricts the effectiveness of various anticancer drugs. Therefore, the development of novel anticancer drugs for the treatment of CRC patients with MDR is necessary. Quaternized thiourea main-chain polymer (QTMP) is a self-assembled nanoparticle with good water solubility. Notably, QTMP is not a P-glycoprotein (P-gp) substrate, and it exhibits potent cytotoxic activity against CRC cells, including HCT116/DDP and P-gp-mediated multidrug-resistant Caco2 cells. QTMP also exhibits a strong anticancer activity against SW480 cells in vivo. Interestingly, reactive oxygen species (ROS) and reactive nitrogen species (RNS) production were increased in a concentration-dependent manner in QTMP-treated HCT116, SW480 and Caco2 cells. Importantly, QTMP causes DNA damage in these CRC cells via direct insertion into the DNA or regulation of ROS and/or RNS production. QTMP also induces caspase-dependent apoptosis via overproduction of ROS and RNS. Therefore, QTMP is a promising anticancer therapeutic agent for patients with CRC, including those cancer cells with P-gp-mediated MDR. The present study also indicates that the design and synthesis of anticancer drugs based on thiourea polymers is promising and valuable, thereby offering a new strategy to address MDR, and provides reference resources for further investigations of thiourea polymers.
Highlights
Colorectal cancer (CRC) is the third leading cause of new cancer cases and the second most frequent cause of cancer-related death [1]
multidrug resistance (MDR) is often associated with the overexpression of P-glycoprotein (P-gp), which is a member of the ATP-binding cassette (ABC) family of efflux transporters, which escalate the efflux of anticancer drugs from cancer cells and lead to a decrease in intracellular drug concentrations [6, 7]
New peaks for methylene and methyl groups at 3.5 and 1.5 ppm were observed, indicating successful polymerization. This process resulted in a high water solubility of Quaternized thiourea main-chain polymer (QTMP), which was suitable for biomedical use
Summary
Colorectal cancer (CRC) is the third leading cause of new cancer cases and the second most frequent cause of cancer-related death [1]. Despite considerable research efforts aimed at developing novel therapeutic approaches against CRC, the frequent occurrence of multidrug resistance (MDR) severely restricts the effectiveness of various anticancer drugs [2, 3]. The development of QTMP Inhibits Colorectal Cancer novel promising and effective anticancer drugs for the treatment of CRC patients with MDR is necessary. MDR is a well-defined phenomenon constituting combined resistance of cancer cells to several anticancer drugs following exposure to one drug [4, 5]. MDR is often associated with the overexpression of P-glycoprotein (P-gp), which is a member of the ATP-binding cassette (ABC) family of efflux transporters, which escalate the efflux of anticancer drugs from cancer cells and lead to a decrease in intracellular drug concentrations [6, 7].
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