Synthetic Phenolic Antioxidant TS-13 Suppresses the Growth of Lewis Lung Carcinoma and Potentiates Oncolytic Effect of Doxorubicin.

E B Men’Shchikova,N V Kandalintseva,P M Kozhin,A V Chechushkov,N K Zenkov,M V Khrapova,A V Kovner,G G Martinovich

doi:10.1007/s10517-019-04410-6

Abstract

ROS are important intracellular messengers; their ambiguous role in malignant processes was demonstrated in many studies. The effects of a synthetic phenolic antioxidant sodium 3-(3'-tert-butyl-4'-hydroxyphenyl)propyl thiosulfonate sodium (TS-13) on the tumor growth and oncolytic properties of doxorubicin were studied in the experimental model of Lewis lung carcinoma in mice. In mice receiving TS-13 with drinking water (100 mg/kg), suppression of tumor growth by 32.3% was observed on day 21 after inoculation of Lewis lung carcinoma cells. Two-fold intraperitoneal injections of doxorubicin in a cumulative dose of 8 mg/kg were followed by inhibition of tumor growth by 49.5%. Combined treatment with TS-13 and doxorubicin suppressed the tumor growth by 55.4%. In contrast to doxorubicin, TS-13 inhibited NO generation by peritoneal macrophages. The results show the prospect of studying TS-13 in the context of overcoming drug-resistance of tumors.

Highlights

ROS are important intracellular messengers; their ambiguous role in malignant processes was demonstrated in many studies
The analysis of the effects of water-soluble sulfurcontaining phenolic antioxidant 3-(3’-tert-butyl-4’hydroxyphenyl)propyl thiosulfonate sodium (TS-13) on the redox-properties and chemoresistance of tumor cells showed that this agent reduces redox-buffer capacity and effective redox-potential; cell sensitivity to doxorubicin increases under these conditions [4]
The anti-tumor effects of TS-13 can be related to its influence on mitochondria, activation of apoptosis-inducing mechanisms [5], and ability to trigger Keap1/Nrf2/ ARE system [3,6]

Summary

Introduction

ROS are important intracellular messengers; their ambiguous role in malignant processes was demonstrated in many studies. The effects of a synthetic phenolic antioxidant sodium 3-(3’-tert-butyl-4’-hydroxyphenyl)propyl thiosulfonate sodium (TS-13) on the tumor growth and oncolytic properties of doxorubicin were studied in the experimental model of Lewis lung carcinoma in mice. In mice receiving TS-13 with drinking water (100 mg/kg), suppression of tumor growth by 32.3% was observed on day 21 after inoculation of Lewis lung carcinoma cells. Redox-signaling, the effect of regulation of cell functional activity is determined by the type and concentration of cell antioxidants, and intracellular localization of ROS-synthetizing systems. On the basis of these results, we proposed a biophysical model of regulation of apoptosis in tumor cells explaining the effects of redox-active antioxidants [4]. The aim of the present study was to confirm the antitumor effects of TS-13 in vivo on the model of Lewis lung carcinoma in mice

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Results