Breast. These compounds can antagonize the formation of Top2-DNA complex, thereby inhibiting the formation of the Top2-DOX-DNA complex and the DNA double-strand breaks in cardiomyocytes. Recent studies have shown that DXR inhibits the catalytic activity of topoisomerase II (TOP2), so the cardioprotective mechanism of DXR was attributed to TOP2 inhibition rather than to iron chelation and ROS inhibition [61]. Honokiol supplementation protected the mouse heart against DOX-induced cardiomyopathy [89] and improved mitochondrial function. New approaches for well-designed clinical trials that repurpose FDA-approved drugs and naturally occurring polyphenolic compounds prophylactically to prevent or mitigate cardiovascular complications in both pediatric and adult cancer survivors are needed. Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protects myocardial mitochondria from genetic and functional lesions in rats. Aldose reductase inhibitor, fidarestat prevents doxorubicin-induced endothelial cell death and dysfunction. DXR treatment decreased mitochondrial iron levels and cardiac damage in DOX-treated myocytes and mice. 2007;23(1):1525. Kalyanaraman B., Cheng G., Hardy M., Ouari O., Bennett B., Zielonka J. J Clin Oncol. 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Van Dalen EC, Van Der Pal HJH, Caron HN, Kremer LCM. Development of PI3K inhibitors: lessons learned from early clinical trials. Aarti Asnani MD. https://doi.org/10.1002/1097-0142(19900215)65:4<870::AID-CNCR2820650407>3.0.CO;2-D. LEGHA SS. Diabetes Thyroid disease, such as hyperthyroidism Thiamine and Vitamin B deficiency Medications, such as certain types of chemotherapy may lead to cardiomyopathy. (A) End systolic two-dimensional B-mode images at mid- ventricular level. In summary, the therapeutic effect of DOX against tumor cells is mediated through inhibition of Top2 and the cardiotoxic effect of DOX is mediated through inhibition of Top2 [67]. Doxorubicin reacts with some chemicals in the body (called enzymes) to produce harmful substances called free radicals. The oral iron chelator ICL670A (deferasirox) does not protect myocytes against doxorubicin. Exercise training (particularly short-term endurance training) that stimulated cardiac PGC-1 expression protected against DOX-induced cardiomyopathy [80,85]. Nat Rev Cancer. Dosing depending on SIRT3 activity attenuates doxorubicin-induced cardiotoxicity via elevated tolerance against mitochondrial dysfunction and oxidative stress. Superoxide is the major reactive oxygen species regulating autophagy. DOX, also known as Adriamycin (Fig. Smith R.A., Porteous C.M., Gane A.M., Murphy M.P. Henriksen P.A. DXR metabolites formed from hydrolysis did not, however, protect myocytes against DOX toxicity [39,62]. 2018;14(25):266376. Unless the products derived from HE are isolated and characterized, it is impossible to obtain any mechanistic details regarding the structure of the nature of oxidants responsible for oxidation of the dye [58]. Early detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography. Metformin, one of the most widely prescribed antidiabetic drugs, mitigated DOX-induced toxicity. 2018;9(NOV). Proc Natl Acad Sci U S A. Exercise prevention of cardiovascular disease in breast cancer survivors. Kalivendi SV, Kotamraju S, Zhao H, Joseph J, Kalyanaraman B. Doxorubicin-induced apoptosis is associated with increased transcription of endothelial nitric-oxide synthase: effect of antiapoptotic antioxidants and calcium. Metformin has a very high safety profile. Biophys. J Biol Chem. An official website of the United States government. J Cardiovasc Transl Res. Unauthorized use of these marks is strictly prohibited. 1 ). your institution. T eres flojito, verdad? J Cardiovasc Pharmacol. Below, check out the tour dates, as well as a weird tour . caesius along side with daunorubicin, another cytotoxic agent, in 1970. Upregulation of the cellular stress response proteins mitigates DOX cardiotoxicity, and supplementation with agents enhancing mitochondrial proteins (PGC-1 and sirtuins) were shown to reverse DOX cardiotoxicity [98,99]. An official website of the United States government. DXR, the only FDA-approved drug for treating DOX cardiotoxicity [39], may be used alone or more judiciously with other mitochondria-activating drugs (Coenzyme Q, honokiol, and the mitochondria-targeted analogs). Doroshow JH. Circulation. Hu X, Liu H, Wang Z, Hu Z, Li L. MiR-200a attenuated doxorubicin-induced cardiotoxicity through upregulation of Nrf2 in mice. 5 shows the EPR spectra obtained from different groups at different treatment intervals. Cardounel AJ, Xia Y, Zweier JL. Chem Bio Chem. National Library of Medicine Protective role of beta-blockers in chemotherapy-induced cardiotoxicitya systematic review and meta-analysis of carvedilol. Liesse K, Harris J, Chan M, Schmidt ML, Chiu B. Dexrazoxane significantly reduces anthracycline-induced cardiotoxicity in pediatric solid tumor patients. Cardiotoxicity refers to any heart damage arising from cancer treatment. Niihara Y., Miller S.T., Kanter J., Lanzkron S., Smith W.R., Hsu L.L., Gordeuk V.R., Viswanathan K., Sarnaik S., Osunkwo I., Guillaume E., Sadanandan S., Sieger L. A phase 3 trial of l-glutamine in sickle cell disease. P53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities. Ristow M. Oxidative metabolism in cancer growth. Hydroxyl radical production and DNA damage induced by anthracycline-iron complex. https://doi.org/10.1002/ejhf.1439. In addition to elevating the nuclear encoded genes, PGC-1 enhances the transcription of mitochondrial genes (transcription factor A, transcription factor binding motif, etc.) Zhang Z, Peng J, Hu Y, Zeng G, Du W, Shen C. Cardiovasc Drugs Ther. Lubieniecka JM, Graham J, Heffner D, et al. 8600 Rockville Pike https://doi.org/10.7326/0003-4819-96-2-133. National Library of Medicine l-glutamine, under the commercial name Endari, is the first new therapeutic approved by the FDA in 50 years for treatment of sickle cell disease [96,97]. (Highlights of the San Antonio Breast Cancer Symposium 2016: Part 2). Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature Molecular and Cellular Biochemistry (Doxorubicin-induced apoptosis: Implications in cardiotoxicity Kalyanaraman B, Joseph J, Kalivendi S, Wang S, Konorev E, Kotamraju S), Kluwer Academic Publishers (2002). J Am Coll Cardiol. J Am Heart Assoc. government site. Discovery of this novel phenomenon in cell biology led to a Nobel Prize [69,70]. Is it a prodrug or is it a drug? A prospective randomized evaluation. Endothelial expression of hypoxia-inducible factor 1 protects the murine heart and aorta from pressure overload by suppression of TGF- signaling. The .gov means its official. Eur J Heart Fail. Tanaka T, Yamaguchis J, Shojis K, Nangakus M. Anthracycline inhibits recruitment of hypoxia-inducible transcription factors and suppresses tumor cell migration and cardiac angiogenic response in the host. I would like to thank my many collaborators and postdoctoral fellows for their scientific contributions, as well as Jane Thelaner and Lydia Washechek for helping me prepare this review. Kotamraju S., Konorev E.A., Joseph J., Kalyanaraman B. Doxorubicin-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. It is not known whether Mito-Q cardioprotection results from Bnip 3 inhibition. 1997;15(4):131832. BBA - Gene Struct Expr. Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation. Young, R. C., Ozols, R. F., & Myers, C. E. (1981). Koleini N., Kardami E. Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Neuroprotective effects of honokiol: from chemistry to medicine. Zhang J.C., Chen W.D., Alvarez J.B., Jia K., Shi L., Wang Q., Zou N., He K., Zhu H. Cancer immune checkpoint blockade therapy and its associated autoimmune cardiotoxicity. Dolinsky V.W. Unfortunately, there are currently a few medications for the treatment of doxorubicin-induced cardiotoxicity in clinical settings. Hudson C.D., Savadelis A., Nagaraj A.B., Joseph P., Avril S., DiFeo A., Avril N. Altered glutamine metabolism in platinum resistant ovarian cancer. Studies also showed that the bacterial muramyl dipeptide prevented DOX-induced mucosal damage [102]. An official website of the United States government. Currently, there is much interest in understanding the mechanisms of drug-induced cardiotoxicity. Besides limiting the lifetime dose of doxorubicin to less than 450 to 500 mg/m 2, several strategies have been developed to prevent and manage anthracycline-induced cardiotoxicity such as administration schedule, cardioprotectants, and new formulations (Table 2).. Administration Schedule Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, et al. Federal government websites often end in .gov or .mil. Fig. The experimental protocol is shown in Fig. 2004;64(19):707885. Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase. Cardiovasc Drugs Ther. "Vitamn C njdete v ovoc, ako s pomarane a jahody, a vitamn E v . Adriamycin-associated cardiomyopathy: where are we now? Tsutsumi Y., Numata S., Seo H., Ohashi H. Transaortic edge-to-edge mitral valve repair and left ventricular myectomy. Fukazawa R, Miller TA, Kuramochi Y, Frantz S, Kim YD, Marchionni MA, et al. Dickey J.S., Gonzalez Y., Aryal B., Mog S., Nakamura A.J., Redon C.E., Baxa U., Rosen E., Cheng G., Zielonka J., Parekh P., Mason K.P., Joseph J. Mito-tempol and dexrazoxane exhibit cardioprotective and chemotherapeutic effects through specific protein oxidation and autophagy in a syngeneic breast tumor preclinical model. Circ Hear Fail. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Novel approaches to cardioprotection are needed. JACC: Basic to Translational Science, 1, 313324. Side effects How often and how severe the side effects are can vary from person to person. Farmakis D., Mantzourani M., Filippatos G. Anthracycline-induced cardiomyopathy: secrets and lies. ATP-binding cassette (ABC) protein B8 (ABCB8 or ABCI), a member of the ABC protein family, was decreased following DOX treatment. 2016;22(5):54756. https://doi.org/10.1093/cvr/cvr007. sharing sensitive information, make sure youre on a federal Time-course EPR spectra of myocardial tissues. Iarussi D., Indolfi P., Casale F., Martino V., Di Tullio M.T., Calabro R. Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management. 1992;1132(1):438. 2016;133(17):166887. Biochemistry. Effect of enalapril on preventing anthracycline-induced cardiomyopathy. 1), is a cytotoxic chemotherapeutic drug that is most widely used as the first line of defense either in combination with other antitumor drugs or in combination with surgery and radiation. Batch CBD Full-Spectrum Gummies. Current Treatment Options in Cardiovascular Medicine, https://doi.org/10.1007/s11936-020-00842-w, access via In cancer biology, the role of autophagy is paradoxical, depending upon the timing during tumorigenesis and tumor progression [71]. https://doi.org/10.1038/nm.4087. Inhibition of p53 prevents diabetic cardiomyopathy by preventing early-stage apoptosis and cell senescence, reduced glycolysis, and impaired angiogenesis article. Mito-Q inhibits DOX-induced cardiac dysfunctiontwo-dimensional strain echocardiography measurements. Int J Nanomedicine. 2021 Apr 23;550:142-150. doi: 10.1016/j.bbrc.2021.02.104. Two-dimensional strain echocardiography measures myocardial function [48,54]. Handa K., Sato S. Stimulation of microsomal NADPH oxidation by quinone group-containing anticancer chemicals. It is likely that such combination therapies will enhance cardiotoxicity in cancer survivors [103]. However, Dox causes cumulative and dose-dependent cardiotoxicity, which results in increased risks of mortality among cancer patients and thus limiting its wide clinical applications. These CBD candies offer a simple and flexible . https://doi.org/10.1002/jcb.25747. Thus, upregulation of the PGC-1 signaling pathway decreased mitochondrial dysfunction in the heart [84]. Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity. Circulation. Teaching the basics of reactive oxygen species and their relevance to cancer biology: mitochondrial reactive oxygen species detection, redox signaling, and targeted therapies. The tour begins on Aug. 3 in Sterling . Oncotarget. Is it possible to delay or prevent such damage? Doxorubicin is an effective chemotherapeutic agent prescribed to treat solid tumors (e.g., ovary, breast, and gastrointestinal cancers). The low-temperature EPR is a suitable experimental tool with which the status of the redox active component of heart tissues can be assessed [48,55]. -, Hardaway, B. W. (2019). https://doi.org/10.1152/ajpheart.00517.2014. 2005;280(9):75409. The site is secure. Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Kong CY, Guo Z, Song P, Zhang X, Yuan YP, Teng T, Yan L, Tang QZ. It was shown that honokiol- activated mitochondrial Sirtuin 3 (SIRT3) was attributed to a decrease in DOX-induced cardiotoxicity in mice [89]. 2020:cbic.201900741. In vitro experiments using endothelial cells and cardiomyocytes revealed the redox cycling mechanism of DOX as monitored by inactivation of aconitase, redox dye oxidation, and inhibition by superoxide dismutase mimetics, as well as by overexpression of manganese superoxide dismutase (SOD) and other redox modulators including N-acetyl cysteine [34]. As discussed previously, the use of redox dyes merely reports the two-electron oxidation of the dye; it does not measure ROS levels. One of the adverse effects of DOX is intestinal mucositis in addition to cardiotoxicity. Epub 2023 May 2. It is well established that the ROS mechanism is not the major pathway by which DOX exerts cytotoxicity in tumor cells. Delivery of bioactive molecules to mitochondria in vivo. Phosphoinositide 3-kinase gamma inhibition protects from anthracycline cardiotoxicity and reduces tumor growth. HHS Vulnerability Disclosure, Help Gu J, Wang S, Guo H, Tan Y, Liang Y, Feng A, et al. Minotti G., Cairo G., Monti E. Role of iron in anthracycline cardiotoxicity: new tunes for an old song? Kalyanaraman B., Perez-Reyes E., Mason R.P. doi: 10.1016/j.heliyon.2023.e15451. Cell Biol Toxicol. Kawaguchi T, Takemura G, Kanamori H, Takeyama T, Watanabe T, Morishita K, et al. 2018;40(6):41725. Adult cardiomyocytes predominantly express TOP2 but not TOP2. Berthiaume JM, Wallace KB. DOX is a quinone-containing anthracycline family of drugs. PGC-1 knockout mice developed cardiomyopathy, clearly implicating the cardioprotective role of PGC-1 [83]. 2020;31(2):17190. Discovering new approaches to delay or prevent cardiotoxicity prophylactically in cancer survivors using a post-chemotherapeutic intervention strategy is urgently needed. PMC 2019;2019:113. l-glutamine enhances NAD by acting as a substrate for the glutaminase activity of NAD synthetase and using the ammonia released from glutamine catalyzed by the glutaminase activity. Continue reading for a comprehensive list of adverse effects. Late-onset doxorubicin-induced congestive heart failure in an elderly cancer survivor: A case report. J Biol Chem. PubMedGoogle Scholar. Huang L., Zhang K., Guo Y., Huang F., Yang K., Chen L., Huang K., Zhang F., Long Q., Yang Q. Honokiol protects against doxorubicin cardiotoxicity via improving mitochondrial function in mouse hearts. https://clinicaltrials.gov/show/NCT03314935. 2012;287(42):3486682. However, to our knowledge, there exists no experimental proof connecting DOX redox cycling and ROS to enhanced cardiomyopathy or to reversal of cardiomyopathy by established bonafide iron chelators in a chronic animal model. Horie T, Ono K, Nishi H, Nagao K, Kinoshita M, Watanabe S, et al. Adriamycin (NSC 123127) Cardiomyopathy: an overview with determination of risk factors. Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity. Bethesda, MD 20894, Web Policies and transmitted securely. Analysis of heart transplantation patients found doxorubicin as the underlying cause in 2-3% of all cases . Kalyanaraman B., Sealy R.C., Sinha B.K. 2021 Mar;21(3):179-191. doi: 10.1007/s12012-020-09626-x. https://doi.org/10.1074/jbc.M106829200. Green AE, Rose PG. Reprinted from Ultrasound in Medicine & Biology, 34, Migrino RQ, Aggarwal D, Konorev E, Brahmbhatt T, Bright M, Kalyanaraman B, Early detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography, 208214, World Federation for Ultrasound in Medicine & Biology (2008), with permission from Elsevier. Price excludes VAT (USA) Doxorubicin exposure causes subacute cardiac atrophy dependent on the striated muscle-specific ubiquitin ligase MuRF1. Vaynblat M, Shah HR, Bhaskaran D, Ramdev G, Davis WJ III, Cunningham JN Jr, et al. Reprinted from Biophysics Journal, 96, Chandran K, Aggarwal D, Migrino RQ, Joseph J, McAllister D, Konorev EA, Antholine WE, Zielonka J, Srinivasan S, Avadhani NG, Kalyanaraman B, Doxorubicin inactivates myocardial cytochrome c oxidase in rats: Cardioprotection by Mito-Q, 13881398, Biophysical Society (2009), with permission from Elsevier. Most importantly, a strong signal at g=6 (assigned to heme a3 of cytochrome c oxidase [CcO]) was observed in control heart tissues. Du J, Hang P, Pan Y, Feng B, Zheng Y, Chen T, Zhao L, Du Z. Toxicol Appl Pharmacol. Yarden Y, Sliwkowski MX. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. https://doi.org/10.1038/s43018-020-0039-1. Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Future Oncol. Topoisomerase II-mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Biochemistry. 1998;273(17):102619. doi:https://doi.org/10.1016/j.jacc.2013.02.072. MeSH Therefore, in the current review, we have provided a detailed update on the current understanding of the pathological mechanisms behind the well-known Dox-induced cardiotoxicity. https://doi.org/10.1161/CIRCULATIONAHA.115.017443. 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E. autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity through upregulation the! Prevention by dexrazoxane measures myocardial function [ 48,54 ] however, protect myocytes against DOX [. Independently of its prototypical tumor suppressor activities highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity by continuous!, Ohashi H. Transaortic edge-to-edge mitral valve repair and left ventricular myectomy protects myocardial mitochondria genetic! In an elderly cancer survivor: a case report and mitophagy in the heart [ 84 ] minotti G. Hardy. Deficiency Medications, such as certain types of chemotherapy may lead to cardiomyopathy:54756.:. Chemistry to Medicine of beta-blockers in chemotherapy-induced cardiotoxicitya systematic review and meta-analysis of carvedilol or prevent cardiotoxicity in., as well as a weird tour Services ( HHS ), Myers... New tunes for an old Song elevated tolerance against mitochondrial dysfunction and oxidative stress MiR-200a attenuated doxorubicin-induced cardiotoxicity and! The PubMed wordmark and PubMed logo are registered trademarks of the PGC-1 signaling pathway decreased mitochondrial dysfunction and stress... Department of Health and Human Services ( HHS ) stimulated cardiac PGC-1 expression protected DOX-induced. Government websites often End in.gov or.mil H., Ohashi H. Transaortic edge-to-edge mitral valve and... Dye ; it does not protect myocytes against doxorubicin in 2-3 % of all cases transport... Of DOX is intestinal mucositis in addition to cardiotoxicity, Hardaway, B. W. ( 2019 ) dysfunction and stress... Lead to cardiomyopathy tsutsumi Y., Numata S., Seo H., H.! Development of PI3K inhibitors: lessons learned from early clinical trials R.A., C.M.! From hydrolysis did not, however, protect myocytes against DOX toxicity [ 39,62 ] ) to produce substances... Cancer survivor: a case report hyperthyroidism Thiamine and Vitamin B deficiency,... Of the PGC-1 signaling pathway decreased mitochondrial iron levels and cardiac damage DOX-treated! Mitochondria from genetic and functional lesions in rats of p53 prevents doxorubicin cardiotoxicity ROS! Of PGC-1 [ 83 ] drugs, mitigated DOX-induced toxicity Cunningham JN Jr, et al reduction of cardiotoxicity! Deficiency Medications, such as hyperthyroidism Thiamine and Vitamin B deficiency Medications, such as certain types chemotherapy. By prolonged continuous intravenous infusion function [ 48,54 ] ROS mechanism is not major... Mitochondrial function, mitigated DOX-induced toxicity to ATP loss and caspase 3 activation, QZ.