Zinc–Carnosine Metallodrug Network as Dual Metabolism Inhibitor Overcoming Metabolic Reprogramming for Efficient Cancer Therapy

Abstract

The targeting of tumor metabolism as a novel strategy for cancer therapy has attracted tremendous attention. Herein, we develop a dual metabolism inhibitor, Zn–carnosine metallodrug network nanoparticles (Zn-Car MNs), which exhibits good Cu-depletion and Cu-responsive drug release, causing potent inhibition of both OXPHOS and glycolysis. Notably, Zn-Car MNs can decrease the activity of cytochrome c oxidase and the content of NAD+, so as to reduce ATP production in cancer cells. Thereby, energy deprivation, together with the depolarized mitochondrial membrane potential and increased oxidative stress, results in apoptosis of cancer cells. In result, Zn-Car MNs exerted more efficient metabolism-targeted therapy than the classic copper chelator, tetrathiomolybdate (TM), in both breast cancer (sensitive to copper depletion) and colon cancer (less sensitive to copper depletion) models. The efficacy and therapy of Zn-Car MNs suggest the possibility to overcome the drug resistance caused by metabolic reprogramming in tumors and has potential clinical relevance.

Noninvasive Imaging of Tumor Glycolysis and Chemotherapeutic Resistance via De Novo Design of Molecular Afterglow Scaffold

“…The first agent, 2-deoxy d -glucose (2-DG), is an inhibitor of hexokinase (HK) which is overexpressed in drug-resistant cells . The second agent, Carnosine, prevents glycolysis by depleting glycolytic intermediates. − We then investigated the effects of these agents on intracellular pH via RAN staining of MCF-7 DR cells incubated with either 2-DG or Carnosine. Flow cytometry analysis of intracellular fluorescence intensity revealed a significant decrease in fluorescence signal in cells treated with both agents compared to PBS-treated cells.…”

“…Furthermore, 2-DG showed a greater effect in upregulating the pH value compared to Carnosine (Figure b). To evaluate the change in intracellular pH, we employed another intracellular pH indicator (BCECF-AM) in identical conditions . Flow cytometry analysis revealed a higher fluorescence intensity of BCECF in cells treated with 2-DG compared to both the Carnosine and control groups.…”

“…To evaluate the change in intracellular pH, we employed another intracellular pH indicator (BCECF-AM) in identical conditions. 71 Flow cytometry analysis revealed a higher fluorescence intensity of BCECF in cells treated with 2-DG compared to both the Carnosine and control groups. This increased fluorescence indicates a greater enhancement of the pH induced by 2-DG (Figure 5c).…”

“…Recently, targeting tumor metabolism as an alternative cancer therapy has gained significant attention. 71 This approach aims to disrupt the metabolic system and cut off nutrient supply as a means to counteract tumor progression. 15 Inhibition of the OXPHOS process in tumor cells triggers a compensatory upregulation of glycolysis to maintain ATP production and meet metabolic demands, particularly the increased energy and biosynthetic requirements associated with cell proliferation.…”

“…However, the research indicates that tumor cells' sensitivity to these inhibitors varies greatly. 15,71 Given the successful measurement of RAN in cancer cells, we attempted to use afterglow imaging to assess the therapeutic efficacy of OXPHOS inhibitors in living mice. Since Tamoxifen demonstrated more effective regulation of pH in cancer cells compared to other agents, we selected Tamoxifen for in vivo tumor regulation.…”