Combined administration of synthetic monophenol TS-13 with doxorubicin enhances the antimitotic effect and mitigates adverse effects of the cytostatic in tumor growth model

Chemotherapy toxicity and tumor chemoresistance remain major challenges in modern oncology. One promising strategy to improve therapeutic efficacy and reduce adverse effects is the use of redox-active compounds that attenuate oxidative stress, in particular by activating the antioxidant-responsive Keap1/Nrf2/ARE signaling pathway. The aim of this study was to evaluate the effects of the synthetic monophenol TS-13, which exhibits both direct and indirect antioxidant activity, on the development and metastasis of Lewis lung carcinoma in mice. Material and methods . A total of 106 female C57BL mice were randomized into 12 groups. For one month, some groups received oral administration of TS-13 or the reference compound tert-butylhydroquinone (tBHQ) (100 mg/kg). Subsequently, selected groups were implanted intramuscularly with 2×105 Lewis lung carcinoma cells. Some animals then received two injections of doxorubicin (total dose 8 mg/kg). After 7 weeks, tumor and lung tissues were processed for standard histological analysis. Tumor growth activity was assessed by counting mitotic figures, and the general morphological characteristics of tumor and lung tissues were described. Results. Both doxorubicin and TS-13 demonstrated marked antimitotic effects, which were further enhanced by their combined administration. Combination therapy with cytostatic and TS-13 more effectively suppressed metastatic activity and reduced the overall area of tumor lesions in the lungs compared to monotherapy with doxorubicin, TS-13, or tBHQ. Administration of either TS-13 or tBHQ equally inhibited the development of lung metastases, reducing the number of tumor cells and the formation of large metastatic foci. Notably, the use of TS-13 in combination with doxorubicin partially restored the integrity of the bronchial epithelium. Conclusions . The synthetic monophenol TS-13, acting as both a direct antioxidant and an activator of the Keap1/Nrf2/ARE pathway, demonstrates potential for optimizing anticancer therapy by enhancing the effect of doxorubicin and suppressing tumor growth and metastasis. In addition, its combined use with doxorubicin helps reduce tissue damage and mitigates the adverse impact on the bronchial epithelium. These properties of TS-13 highlight its prospects for reducing side effects and improving the efficacy of standard chemotherapy regimens.