Thiosemicarbazide Derivatives Targeting Human TopoIIα and IDO-1 as Small-Molecule Drug Candidates for Breast Cancer Treatment

Sep 24, 2026

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Investigates thiosemicarbazide derivatives as dual inhibitors of human DNA topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO-1) for breast cancer therapy. Compounds 1–3 selectively suppress proliferation of MCF-7 and MDA-MB-231 cells, promote apoptosis through caspase-8- and caspase-9-related pathways, and induce S-phase cell-cycle arrest. They dose-dependently inhibit MDR1, MRP1/2, and BCRP transporter activity and increase autophagic cell numbers after exposure to compound 1. Preliminary ADME-Tox testing evaluates hemolytic potential and effects on cytochrome P450 enzymes.

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CategoryResearch & Report

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Abstract

1. Introduction

Article Thiosemicarbazide Derivatives Targeting Human TopoII􀀋 and IDO-1 as Small-Molecule Drug Candidates for Breast Cancer Treatment Barbara Kapro ´n 1, Robert Czarnomysy 2, Dominika Radomska 2, Krzysztof Bielawski 2 and Tomasz Plech 3, * Citation: Kapro ´n, B.; Czarnomysy, R.; Radomska, D.; Bielawski, K.; Plech, T. Thiosemicarbazide Derivatives Targeting Human TopoII􀀋 and IDO-1 as Small-Molecule Drug Candidates for Breast Cancer Treatment. Int. J. Mol. Sci. 2023, 24, 5812 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24065812 Academic Editor: Francisco Estevez Received: 30 December 2022 Revised: 13 March 2023 Accepted: 15 March 2023 Published: 18 March 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Clinical Genetics, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland 2 Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Kili ´nskiego 1, 15-089 Białystok, Poland 3 Department of Pharmacology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland * Correspondence: tomasz.plech@umlub.pl; Tel.: +48-81-448-67-72 Abstract: In 2020, breast cancer became the most frequently diagnosed type of cancer, with nearly 2.3 million new cases diagnosed. However, with early diagnosis and proper treatment, breast cancer has a good prognosis. Here, we investigated the effect of thiosemicarbazide derivatives, previously identiﬁed as dual inhibitors targeting topoisomerase II􀀋 and indoleamine-2,3-dioxygenase 1 (IDO 1), on two distinct types of breast cancer cells (MCF-7 and MDA-MB-231) . The investigated compounds (1–3) selectively suppressed the growth of breast cancer cells and promoted apoptosis via caspase-8-and caspase-9-related pathways. Moreover, these compounds caused S-phase cell cycle arrest and dose-dependently inhibited the activity of ATP-binding cassette transporters (MDR1, MRP1/2 and BCRP) in MCF-7 and MDA-MB-231 cells. Additionally, following incubation with compound 1, an increased number of autophagic cells within both types of the investigated breast cancer cells was observed. During preliminary testing of ADME-Tox properties, the possible hemolytic activities of compounds 1–3 and their effects on speciﬁc cytochrome P450 enzymes were evaluated. Keywords: breast cancer; thiosemicarbazide derivatives; dual-targeting agents; ﬂow cytometry; ADME-Tox 1. Introduction Currently, cancer is recognized as a leading cause of death worldwide, being responsible for 10 million deaths in 2020 [1] . Additionally, in the same year, breast cancer (BC) became the most frequently diagnosed type of cancer, with nearly 2.3 million new cases. However, with early diagnosis and proper treatment, BC has a good prognosis. One of the most widely recognized classiﬁcations of BC is based on the immunohistochemical expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptors (HER2) . Among the four classiﬁed subtypes of BC, luminal A and luminal B subtypes are ER and/or PR positive and the HER2 subtype is characterized by high HER2 expression and a lack of ER/PR, while triple-negative BC (TNBC) is characterized by the absence of ER/PR and HER2 overexpression [2] . Depending on the type and grade of BC, its treatment includes surgery, radiation and systemic therapy (chemotherapy, hormone therapy, immunotherapy and targeted biological therapy) . Pharmacological treatment can be applied before or after the surgical intervention, i.e., as neoadjuvant or adjuvant therapy, respectively. The main objective of chemotherapy in BC is to destroy cancer ce

FAQs

What drug targets do the thiosemicarbazide derivatives address in this study?

They are designed as dual inhibitors targeting human DNA topoisomerase IIα and IDO-1.

How do compounds 1–3 affect breast cancer cells (MCF-7 and MDA-MB-231)?

They selectively suppress growth, promote apoptosis via caspase-8- and caspase-9-related pathways, and cause S-phase cell-cycle arrest.

What additional mechanisms and safety-related aspects are evaluated?

The compounds inhibit ATP-binding cassette transporters (MDR1, MRP1/2, BCRP) and compound 1 increases autophagic cells; preliminary ADME-Tox testing includes hemolytic activity assessment and cytochrome P450 enzyme effects.

Sep 24, 2026

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