Black Phosphorus Quantum Dots Enhance the Radiosensitivity of Human Renal Cell Carcinoma Cells through Inhibition of DNA-PKcs Kinase

Abstract

Renal cell carcinoma (RCC) is one of the most aggressive urological malignancies and has a poor prognosis, especially in patients with metastasis. Although RCC is traditionally considered to be radioresistant, radiotherapy (RT) is still a common treatment for palliative management of metastatic RCC. Novel approaches are urgently needed to overcome radioresistance of RCC. Black phosphorus quantum dots (BPQDs) have recently received great attention due to their unique physicochemical properties and good biocompatibility. In the present study, we found that BPQDs enhance ionizing radiation (IR)-induced apoptotic cell death of RCC cells. BPQDs treatment significantly increases IR-induced DNA double-strand breaks (DSBs), as indicated by the neutral comet assay and the DSBs biomarkers γH2AX and 53BP1. Mechanistically, BPQDs can interact with purified DNA–protein kinase catalytic subunit (DNA-PKcs) and promote its kinase activity in vitro. BPQDs impair the autophosphorylation of DNA-PKcs at S2056, and this site phosphorylation is essential for efficient DNA DSBs repair and the release of DNA-PKcs from the damage sites. Consistent with this, BPQDs suppress nonhomologous end-joining (NHEJ) repair and lead to sustained high levels of autophosphorylated DNA-PKcs on the damaged sites. Moreover, animal experiments indicate that the combined approach with both BPQDs and IR displays better efficacy than monotreatment. These findings demonstrate that BPQDs have potential applications in radiosensitizing RCC cells.

Effective strategies to enhance the diagnosis and treatment of RCC: The application of biocompatible materials

“…Nevertheless, scholars persist in investigating the underlying mechanisms of resistance to these treatment modalities and endeavor to identify strategies for enhancing sensitivity. In their study on radiotherapy, Shang et al discovered that black phosphorus quantum dots (BPQDs) have the ability to enhance the kinase activity of purified DNA protein kinase catalytic subunits (DNA-PKcs) in vitro, resulting in a significant increase in autophosphorylation of DNA-PKcs by inhibiting non-homologous end-joining repair [ 167 ]. This phenomenon ultimately led to a heightened number of ionizing radiation (IR)-induced breaks in DNA double strands by BPQDs, thereby greatly enhancing the efficacy of radiotherapy for the treatment of RCC.…”

Nanomedicine for renal cell carcinoma: imaging, treatment and beyond

“…DNA is the principle cellular target for the biological effects of ionizing radiation. Yue Lang et al found that black phosphorus quantum dots (BPQDs) inhibit DNA-PKcs activity and impair DNA-PKcs-mediated nonhomologous end joining DNA double-strand breaks repair, resulting in sustained DNA damage in response to ionizing radiation [ 104 ]. BPQDs enhances ionizing radiation -induced suppression of RCC xenografts growth in vivo.…”

Current applications of nanomaterials in urinary system tumors

“…Black phosphorus QDs (BP-QDs) can enhance the apoptosis of RCC cells after ionizing radiation (IR), indicating that BP-QDs have potential application value in the RCC radiosensitization therapy ( Lang et al, 2022 ). Researchers have measured the expression of the proteins Tiam1 and Rac1 in RCC using immunohistochemistry (IHC) and QD labeling methods.…”