An NIR‐Fluorophore‐Based Inhibitor of SOD1 Induces Apoptosis by Targeting Transcription Cofactor PC4

Abstract

AbstractColorectal cancer (CRC) is one of the leading causes of cancer‐related death worldwide. Development of novel therapies has focused on new oncogenes and few tumor‐targeted theranostic agents. Recent studies show that the increased oxidative stress that results from abnormal metabolism makes cancer cells more dependent on antioxidant systems, indicating a proper therapeutic target. As a major antioxidant enzyme, superoxide dismutase 1 (SOD1) is overexpressed in cancer cells and closely related to carcinogenesis and therapeutic effects. However, there is still a lack of tumor‐targeted agents to effectively inhibit the expression of SOD1. Here, a novel near‐infrared heptamethine cyanine dye, IR‐37, is designed, synthesized, and screened that preferentially accumulates in tumor cells with an intrinsic structure‐inherent targeting property, significantly inhibits the expression of SOD1 and induces excessive reactive oxygen species (ROS)‐mediated apoptosis. IR‐37 also has excellent optical properties, implying its potential application in tumor‐targeted imaging. Moreover, a novel CRC‐related oncogene, positive cofactor 4 (PC4), is identified that is involved in the killing effects of IR‐37 through the SOD1‐ROS‐c‐Jun N‐terminal kinase (JNK) pathway. Together, these findings suggest that IR‐37 may be a promising theranostic agent for personalized tumor‐targeted therapy and imaging, and that PC4 is a novel oncogene for the diagnosis and therapy of CRC.