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

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.

Microarray data reveal potential genes that regulate triple-negative breast cancer

“… 10 Previous studies have also shown that increased levels of cell cycle-related proteins are correlated with worse survival in BC patients. 11 A recent study demonstrated that mitochondria are a potential target for drug resistance in TNBC, 12 while another revealed that inhibiting mitochondrial oxidative phosphorylation prevented tumorigenesis of BC cells without interfering with the metabolism of non-cancerous cells. 13 Taken together, these observations are consistent with our results.…”

Membrane Partitioning of TEMPO Discriminates Human Lung Cancer from Neighboring Normal Cells

“…The current study has direct clinical value. TEMPO and its derivatives show significant anti-cancer effects when applied to various types of cancer, including lung cancer [42][43][44][45][46][47]. It is highly anticipated that TEMPO-benzoate, which shows significantly enhanced partitioning in liposome studies [26,27], will also be very effective in the membranes of the corresponding cells.…”

Editorial for the Special Issue “New Drugs for Breast Cancer Treatment”

“…In particular, the readers of this Special Issue will learn about the anti-tumor activity of neosynthesized, natural, and already-available drugs that could be used as new anti-BC drugs. Indeed, the contributing authors have reported the antiproliferative activity of berberine and troglitazone derivatives, resveratrol analogs, atoquavone, clotrimazole, fenticonazole, compounds specifically targeting mitochondrial activity, and valproic acid, as well as NAMPT and carbonic anhydrase IX inhibitors [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”