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

Abstract

Colorectal 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.