Enhance Mitochondrial Damage by Nuclear Export Inhibition to Suppress Tumor Growth and Metastasis with Increased Antitumor Properties of Macrophages

Abstract

Mitochondria-targeting damage has become a popular therapeutic option for tumor metastasis; however, its efficacy is limited by the adaptive rescue capacity of nuclei. There is an urgent need for a dual mitochondrial and nuclear targeting strategy that can also increase the antitumor capacity of macrophages. In this study, XPO1 inhibitor KPT-330 nanoparticles were combined with mitochondria-targeting lonidamine (TPP-LND) nanoparticles. The combination of nanoparticles with a 1:4 ratio of KPT and TL demonstrated the best synergistic effect in restraining the proliferation and metastasis of 4T1 breast cancer cells. Investigating the mechanisms both in vitro and in vivo, it was found that KPT nanoparticles not only directly impede tumor growth and metastasis by controlling the expression of associated proteins but also indirectly facilitate mitochondrial damage. The two nanoparticles synergistically decreased the expression of cytoprotective factors, such as Mcl-1 and Survivin, causing mitochondrial dysfunction and thus inducing apoptosis. Additionally, it downregulated metastasis-related proteins like HIF-1α, vascular endothelial growth factor (VEGF), and matrix metalloproteinase 2 (MMP-2) and reduced endothelial-to-mesenchymal transition. Significantly, their combination increased the ratio of M1 tumor-associated macrophages (TAMs)/M2 TAMs both in vitro and in vivo and increased the phagocytosis of tumor cells by macrophages, thus suppressing tumor growth and metastasis. In summary, this research revealed that nuclear export inhibition can synergistically enhance the prevention of mitochondrial damage to tumor cells, heightening the antitumor properties of TAMs, thereby providing a viable and safe therapeutic approach for the treatment of tumor metastasis.

Single-Atom Nanoenzyme-Based Autoluminescence System for Cancer Cell Imaging and Mitochondrial-Targeted Therapy

“…According to previous studies, tumor metastasis is responsible for almost 90% of cancer-related deaths . Mitochondria produce nearly 95% of cellular ATP which actively supplies energy to encourage tumor development and metastasis. − Besides, the high intratumoral oxygen consumption in cancer cells is due to strong aerobic respiration by the mitochondria, resulting in a hypoxia environment which further enhances tumor metastasis. , Hence, it has been confirmed that mitochondria participate throughout the tumor metastasis process, and mitochondrial-targeted damage has been developed as a popular strategy in the treatment of tumors . To date, more and more drugs have been developed to target mitochondria [e.g., triphenyl phosphonium, TPP + , Ru 2+ , and glycyrrhetinic acid (GA)] .…”

The role of angiogenic growth factors in the immune microenvironment of glioma

“…Through activation of PI3K/Akt/ Nrf2 pathway in GBM cells, VEGF produced by M2 GAMs promotes GBM cell stemness, proliferation, epithelialmesenchymal transition (EMT), and temozolomide resistance (51,53). VEGF downregulation caused by mitochondrial damage in tumor cells resulted in an increased rate of M1/M2 macrophages both in vivo and in vitro, which enhances the TAM effects to st r e n g t h e n t h e im m u n i t y t o a g a i ns t t u m o r s in th e microenvironment (54).…”