Putative anticancer potential of novel 4-thiazolidinone derivatives: cytotoxicity toward rat C6 glioma in vitro and correlation of general toxicity with the balance of free radical oxidation in rats

Abstract

AimTo evaluate the cytotoxic action of 4-thiazolidinone derivatives (ID 3288, ID 3882, and ID 3833) toward rat glioma C6 cells and to compare the effects of these compounds and doxorubicin on the balance of free radical oxidation (FRO) and antioxidant activity (AOA) in the serum of rats.MethodsGlioma cells were treated with ID 3882, ID 3288, ID 3833, and doxorubicin, and their cytotoxicity was studied using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and Trypan blue exclusion test, light and fluorescent microscopy, and flow cytometric study of cell cycling and apoptosis, including measuring of Annexin V-positive cells. The contents of superoxide radical, hydrogen peroxide, hydroxyl radical, malonic dialdehyde, and hydrogen sulfide were measured in the serum of rats. Enzymatic activity of superoxide dismutase (SOD), catalase (Cat), and glutathione peroxydase (GPO) was determined.ResultsAmong novel 4-thiazolidinone derivatives, ID 3288 was most toxic toward rat glioma C6 cells, even compared with doxorubicin. All applied derivatives were less active than doxorubicin in inducing reactive oxygen species-related indicators in the serum of rats. A similar effect was observed when enzymatic indicators of AOA processes were measured. While doxorubicin inhibited the activity of SOD, GPO, and Cat, the effects of 4-thiazolidinone derivatives were less prominent.ConclusionNovel 4-thiazolidinone derivatives differ in their antineoplastic action toward rat glioma C6 cells, and ID 3288 possesses the highest activity compared to doxorubicin. Measurement of indicators of FRO and AOA in the serum of rats treated with these compounds showed their lower general toxicity compared with doxorubicin’s toxicity.

Indicators of oxidative and nitrosative stress and activity of enzymes of nitric oxide metabolism in rats treated with 4-thiazolidinone derivatives possessing antineoplastic activity

“…In vitro evaluation of the vitality and survival (MTT assay and Trypan blue exclusion test) of treated cells revealed the following ranking of toxicity of 4-thiazolidinone derivatives towards C6 rat and U251 human glioma cells: 3882 < 3288 < 3833 ≈ doxorubicin [14,25]. In vivo study (rats) of the biochemical indicators of cardio- [26], hepato- [13] and nephrotoxic [27] actions of the applied drugs showed the same ranking.…”

“…The activation of FRO leads to a pathological process causing the frequent intoxication of the organism [13,14]. The results of studying the effect of experimental compounds (4-thiazolidinone derivatives -Les-3288, Les-3833 and Les-3882) on ROS and RNS concentration in blood serum of rats are shown on Fig.…”

“…Cytotoxicity of the above mentioned compounds towards 60 human tumor cell lines has been evaluated, and three compounds (Les-3288, Les-3833 and Les-3882) posses sing high cytotoxic action towards tumor cells were selected for more detailed analysis of the perspectives of their use as the antineoplastic agents. Studies of the biochemical mechanisms of their cytotoxic effects in vitro have been started, and their biocompati bility in vivo has been evaluated [13,14,16]. The results of such study will contribute to a better understanding of the ways of circumventing negative side effects by the oxidative stress appearing at the action of anticancer drugs with maximum preser ving of their therapeutic efficacy.…”

“…It should be noted that the use of most existing therapies in oncology is accompanied by the development of harmful effects of FRO on the cells of normal tissues and organs [1,5,6,[11][12][13]. These negative side effects are mostly caused by ROS and RNS that significantly limits the applied dosage of appropriate anticancer drugs [1,5,6,12,14]. Therefore, the oxidation-reduction balance in cells is an important biochemical target at the elimination of tumor cells.…”

Differential pro-apoptotic effects of synthetic 4-thiazolidinone derivative Les-3288, doxorubicin and temozolomide in human glioma U251 cells

“…In another study, we have demonstrated the pro-apoptotic action of the Les-3288 compound toward rat glioma cells of C6 line that possessed even higher toxicity for these cells than that of the Dox (25). In present study, we addressed the mechanisms of the pro-apoptotic action of the compound Les-3288, TMZ and Dox in order to reveal potential differences in these mechanisms and, thus, consider them at planning the combined chemotherapy schemes for glioma treatment.…”