Abstract
The biological properties of doxyl stearate nitroxides (DSs): 5-DS, Met-12-DS, and 16-DS, commonly used as spin probes, have not been explored in much detail so far. Furthermore, the influence of DSs on the cellular changes induced by the anticancer drug doxorubicin (DOX) has not yet been investigated. Therefore, we examined the cytotoxicity of DSs and their ability to induce cell death and to influence on fluidity and lipid peroxidation (LPO) in the plasma membrane of immortalised B14 fibroblasts, used as a model neoplastic cells, susceptible to DOX-induced changes. The influence of DSs on DOX toxicity was also investigated and compared with that of a natural reference antioxidant α-Tocopherol. By employing the trypan blue exclusion test and double fluorescent staining, we found a significant level of cytotoxicity for DSs and showed that their ability to induce apoptosis and modify plasma membrane fluidity (measured fluorimetrically) is more potent than for α-Tocopherol. The most cytotoxic nitroxide was 5-DS. The electron paramagnetic resonance (EPR) measurements revealed that 5-DS was reduced in B14 cells at the fastest and Met-12-DS at the slowest rate. In the presence of DOX, DSs were reduced slower than alone. The investigated compounds, administered with DOX, enhanced DOX-induced cell death and demonstrated concentration-dependent biphasic influence on membrane fluidity. A-Tocopherol showed weaker effects than DSs, regardless the mode of its application—alone or with DOX. High concentrations of α-Tocopherol and DSs decreased DOX-induced LPO. Substantial cytotoxicity of the DSs suggests that they should be used more carefully in the investigations performed on sensitive cells. Enhancement of DOX toxicity by DSs showed their potential to act as chemosensitizers of cancer cells to anthracycline chemotherapy.
Highlights
Doxorubicin (DOX) is an anthracycline anticancer drug commonly used in chemotherapy [1].Biological and antitumour actions of DOX are multifactorial and involve its influence on different structures and processes in the cells [2]
We examined the performance of doxyl stearate nitroxides (DSs): 5-doxyl-stearic acid (5-DS; Figure 1A), methyl 12-doxyl-stearate (Met-12-DS; Figure 1B), and 16-doxyl-stearic acid
Our study showed that 5-DS, Met-12-DS, and 16-doxyl-stearic acid (16-DS), as well as a reference compound α-Tocopherol, can trigger apoptosis, which intensity increased with an increase in compound concentrations
Summary
Doxorubicin (DOX) is an anthracycline anticancer drug commonly used in chemotherapy [1]. Biological and antitumour actions of DOX are multifactorial and involve its influence on different structures and processes in the cells [2]. DOX influence on cells starts at the sites of its interactions with components of the cellular membrane. Its binding to the cell membrane primarily depends on hydrophobic and electrostatic interactions with lipids, which determine, i.a., diffusion and efflux of Molecules 2020, 25, 5138; doi:10.3390/molecules25215138 www.mdpi.com/journal/molecules. Molecules 2020, 25, 5138 the drug [3]. DOX evokes perturbations in cell membrane structure and, depending on concentration, causes an increase or a decrease in membrane fluidity [4,5]. It is well known that changes in the cell membrane may affect cell functions and trigger cell death [6]
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