New Amides and Phosphoramidates Containing Selenium: Studies on Their Cytotoxicity and Antioxidant Activities in Breast Cancer

Abstract

Breast cancer is a multifactor disease, and many drug combination therapies are applied for its treatment. Selenium derivatives represent a promising potential anti-breast cancer treatment. This study reports the cytotoxic activity of forty-one amides and phosphoramidates containing selenium against five cancer cell lines (MCF-7, CCRF-CEM, HT-29, HTB-54 and PC-3) and two nonmalignant cell lines (184B5 and BEAS-2B). MCF-7 cells were the most sensitive and the selenoamides I.1f and I.2f and the selenium phosphoramidate II.2d, with GI50 values ranging from 0.08 to 0.93 µM, were chosen for further studies. Additionally, radical scavenging activity for all the compounds was determined using DPPH and ABTS colorimetric assays. Phosphoramidates turned out to be inactive as radical scavengers. No correlation was observed for the antioxidant activity and the cytotoxic effect, except for compounds I.1e and I.2f, which showed dual antioxidant and antitumor activity. The type of programmed cell death and cell cycle arrest were determined, and the results provided evidence that I.1f and I.2f induced cell death via autophagy, while the derivative II.2d provoked apoptosis. In addition, Western blot analysis corroborated these mechanisms with an increase in Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels for I.1f and I.2f, as well as an increase in BAX, p21 and p53 accompanied by a decrease in BCL-2 levels for derivative II.2d.

Novel Selenoesters as a Potential Tool in Triple-Negative Breast Cancer Treatment

“…Previously, it was shown that selenium compounds have been known to be highly cytotoxic toward a variety of cancer cell lines [ 12 , 19 , 40 , 41 , 42 ]. In this study, we demonstrated that both EDA-71 and E-NS-4 selenium compounds exhibited cytotoxic activity on breast cancer cell lines (MCF-7 and MDA-MB-231), with IC 50 values in terms of low micromolar concentrations (1.4 to 4.52 µM).…”

“…High cytotoxic activity can lead to cell death by several significantly different death pathways—apoptosis, entosis, necrosis, necroptosis (regulated necrosis), and autophagy—and the type of cell death depends on the properties of the chemical compound used or the dose applied [ 12 , 16 , 40 , 42 ]. The study by Shigemi et al [ 47 ] showed that Se compounds direct cancer cells mainly to the apoptosis pathway.…”

“…The process of Se-activated apoptosis can follow an intrinsic (mitochondrial) and extrinsic (receptor) pathway [ 12 , 40 , 42 , 47 ]. In the intrinsic pathway of apoptosis, a decrease in mitochondrial membrane potential, release of cytochrome c, and an increase in caspase 9 and caspase 3 activity can be observed [ 23 , 32 , 49 ].…”

“…In the intrinsic pathway of apoptosis, a decrease in mitochondrial membrane potential, release of cytochrome c, and an increase in caspase 9 and caspase 3 activity can be observed [ 23 , 32 , 49 ]. The mechanism of action of numerous selenoorganic compounds is related to the activation of the mitochondrial apoptotic pathway [ 42 , 47 ]. The study of Se derivative—ebselen—performed by Zhang et al [ 50 ] revealed a decrease in mitochondrial membrane potential, release of cytochrome c, and an increase in caspase 9 activity for human multiple myeloma U266 and RPMI8226 cells.…”

“…Therapy with selenium compounds can affect the activity and levels of numerous proteins, including those important in apoptosis and autophagy [ 12 , 42 , 47 ]. A study conducted in 2015 by Wu et al [ 54 ] showed that mTOR protein levels may be downregulated during Se-allylselenocysteine therapy, possibly due to AMPK protein inhibition.…”