Cytostatic Effect of a Novel Mitochondria-Targeted Pyrroline Nitroxide in Human Breast Cancer Lines.

Kitti Andreidesz,Zita Bognar,Eszter Vamos,Mostafa Isbera,Dominika Kovacs,Viola Bagone Vantus,Aliz Szabo,Ferenc Gallyas,Tamas Kalai,Krisztina Kovacs,Balazs Koszegi

doi:10.3390/ijms22169016

Kitti Andreidesz, Zita Bognar + Show 9 more

Open Access

https://doi.org/10.3390/ijms22169016

Copy DOI

Abstract

Mitochondria have emerged as a prospective target to overcome drug resistance that limits triple-negative breast cancer therapy. A novel mitochondria-targeted compound, HO-5114, demonstrated higher cytotoxicity against human breast cancer lines than its component-derivative, Mito-CP. In this study, we examined HO-5114′s anti-neoplastic properties and its effects on mitochondrial functions in MCF7 and MDA-MB-231 human breast cancer cell lines. At a 10 µM concentration and within 24 h, the drug markedly reduced viability and elevated apoptosis in both cell lines. After seven days of exposure, even at a 75 nM concentration, HO-5114 significantly reduced invasive growth and colony formation. A 4 h treatment with 2.5 µM HO-5114 caused a massive loss of mitochondrial membrane potential, a decrease in basal and maximal respiration, and mitochondrial and glycolytic ATP production. However, reactive oxygen species production was only moderately elevated by HO-5114, indicating that oxidative stress did not significantly contribute to the drug’s anti-neoplastic effect. These data indicate that HO-5114 may have potential for use in the therapy of triple-negative breast cancer; however, the in vivo toxicity and anti-neoplastic effectiveness of the drug must be determined to confirm its potential.

Highlights

The sulforhodamine B (SRB) assay measures protein content that is considered to be more proportional to the cell count than metabolic activity, which can under- or over-estimate the cell count if the studied substance inhibits or uncouples mitochondrial oxidative phosphorylation [16]
In agreement with the view that triple-negative breast cancer (TNBC) is more chemotherapy-resistant than HR+BC, the MDA-MB-231 cells were more resistant against HO-5114 treatment than the MCF7 cells, the treatment with 10 μM HO-5114 reduced viability below 10% in both cell lines (Figure 1)
The energy metabolism of the two breast cancer subtypes differs profoundly, which is indicated by the opposite effect of mitochondrial rescue on glycolytically inhibited HR+BC and TNBC cells; it is negative for the former and positive for the latter [10]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Mitochondria have become novel targets for anti-cancer strategies [1]. While the Warburg effect states that due to defective oxidative phosphorylation, the rate of glycolysis is elevated to replace ATP loss [2], oxidative phosphorylation has been recently recognized to play an important role in oncogenesis. The mitochondria of cancer cells can alternate between glycolysis and oxidative phosphorylation to meet the metabolic demands of the cell and to promote survival [3]. Targeting the mitochondria shows great promise to enhance the efficiency of anti-cancer drugs. Targeting the mitochondria could mitigate treatment resistance, another crucial factor of today’s anticancer therapy. Mitochondria-targeted nanocarriers and drugs conjugated to mitochondriatargeting ligands are the most common approaches [4]

Methods

Results

Conclusion