Thioredoxin Decreases Anthracycline Cardiotoxicity, But Sensitizes Cancer Cell Apoptosis
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Thioredoxin Decreases Anthracycline Cardiotoxicity, But Sensitizes Cancer Cell Apoptosis Kumuda C. Das1 · Harish Muniyappa1 · Venkatesh Kundumani‑Sridharan1 · Jaganathan Subramani1 Received: 29 May 2020 / Accepted: 20 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Cardiotoxicity is a major limitation for anthracycline chemotherapy although anthracyclines are potent antitumor agents. The precise mechanism underlying clinical heart failure due to anthracycline treatment is not fully understood, but is believed to be due, in part, to lipid peroxidation and the generation of free radicals by anthracycline-iron complexes. Thioredoxin (Trx) is a small redox-active antioxidant protein with potent disulfide reductase properties. Here, we present evidence that cancer cells overexpressing Trx undergo enhanced apoptosis in response to daunomycin. In contrast, cells overexpressing redox-inactive mutant Trx were not effectively killed. However, rat embryonic cardiomyocytes (H9c2 cells) overexpressing Trx were protected against daunomycin-mediated apoptosis, but H9c2 cells with decreased levels of active Trx showed enhanced apoptosis in response to daunomycin. We further demonstrate that increased level of Trx is specifically effective in anthracycline toxicity, but not with other topoisomerase II inhibitors such as etoposide. Collectively these data demonstrate that whereas high levels of Trx protect cardiomyocytes against anthracycline toxicity, it potentiates toxicity of anthracyclines in cancer cells. Keywords Anthracycline · Doxorubicin · Cardiotoxicity · Redox-cycling · Thioredoxin · Cardiomyocytes · Chemotherapy
Introduction Anthracyclines are highly potent chemotherapeutic agents that have been widely used in the treatment of leukemia, lymphoma, breast cancer, lung cancer, ovarian cancer, thyroid cancer, neuroblastoma, Wilms’ tumor, acute lymphoblastic leukemia and many other types of cancers including treatment of childhood cancers [1–3]. In addition, anthracyclines are major components of several multidrug regimens for metastatic breast carcinoma (MBC), Hodgkin’s disease (HD), lung cancers and leukemia’s. For example, the most widely used combination for MBC being doxorubicin with cyclophosphamide and 5-fluorouracil (5-FU), commonly designated FAC or CAF [4], and epirubicin with cyclophosphamide and 5-FU, commonly designated FEC [5]. Handling editor: Vittorio Fineschi. * Kumuda C. Das [email protected] 1
Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, MS 6598, Lubbock TX 79430, USA
Additionally, ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) is both more effective and less toxic than other regimens used in HD disease [6]. This regimen has become the current standard for the treatment of advanced HD. In addition, anthracyclines are also used in childhood cancers; however, some of survivors of childhood cancers treated with anthracyclines develop clinical heart failure (CHF) or other cardiac complications
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