Abstract
Mitochondrial dysfunction may cause cancer and metabolic syndrome. Ellagic acid (abbreviated as E), a phytochemical, possesses anticancer activity. MicroRNA 125 (miR-125) may regulate metabolism. However, E has low aqueous solubility, and miR-125 is unstable in a biological fluid. Hence, this study aimed to develop nanoparticle formulations for the co-treatment of miR-125 and E. These nanoparticles were modified with one mitochondrion-directed peptide and a tumor-targeted ligand, and their modulating effects on mitochondrial dysfunction, antitumor efficacy, and safety in head and neck cancer (HNC) were evaluated. Results revealed that miR-125- and E-loaded nanoparticles effectively targeted cancer cells and intracellular mitochondria. The co-treatment significantly altered cellular bioenergetics, lipid, and glucose metabolism in human tongue squamous carcinoma SAS cells. This combination therapy also regulated protein expression associated with bioenergenesis and mitochondrial dynamics. These formulations also modulated multiple pathways of tumor metabolism, apoptosis, resistance, and metastasis in SAS cells. In vivo mouse experiments showed that the combined treatment of miR-125 and E nanoparticles exhibited significant hypoglycemic and hypolipidemic effects. The combinatorial therapy of E and miR-125 nanoparticles effectively reduced SAS tumor growth. To our best knowledge, this prospective study provided a basis for combining miRNA with a natural compound in nanoformulations to regulate mitochondrial dysfunction and energy metabolism associated with cancer.
Highlights
Epithelial–mesenchymal transition (EMT) and chemoresistance are two major challenges of the successful treatment of various tumors, such as oral squamous cell carcinoma (OSCC), a type of head and neck cancer (HNC) [1]
Our result indicated that PINK1/Parkin was upregulated, whereas tumor necrosis factor receptor associated protein 1 (TRAP1) was downregulated in response to the treatment of E/lipid-polymer nanoparticles (LPNs)-KL and miR125/solid lipid nanoparticles (SLN)-KL (Figure 4d)
We developed epidermal growth factor receptor (EGFR)-targeting and mitochondrion-directed nanoparticles to incorporate E and MicroRNA 125 (miR-125) for the modulation of lipid and glucose metabolism, mitochondrial oxidative stress, remodeling, bioenergenesis, mitophagy, and fusion/fission dynamics
Summary
Epithelial–mesenchymal transition (EMT) and chemoresistance are two major challenges of the successful treatment of various tumors, such as oral squamous cell carcinoma (OSCC), a type of head and neck cancer (HNC) [1]. Mitophagy has become a potential anticancer target by triggering mitochondrial dysfunction in cancer cells because of the imperative role of mitophagy on mitochondrial homeostasis and cell survival. Dysfunctional mitochondria with reduced mitochondrial membrane potential (MMP) may activate PINK1 and trigger Parkin to be overexpressed on the surfaces of the mitochondria, thereby inducing mitophagy [6]. PINK1/Parkin- dependent mitophagy plays an important role in mitochondrial homeostasis [7], and the modulation of PINK1/Parkin-mediated mitophagy alters the sensitivity of multidrug-resistant cancer cells to anticancer agents [8]. Zinc oxide nanoparticles increase the intracellular levels of reactive oxygen species (ROS) and reduce the MMP, but these nanoparticles stimulate the PINK1/Parkin-mediated mitophagy to induce the anticancer activity in tongue cancer CAL 27 cells [13]. The role of mitophagy in cancer progression or inhibition should be clarified
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