Doxorubicin-induced cardiotoxicity is suppressed by estrous-staged treatment and exogenous 17β-estradiol in female tumor-bearing spontaneously hypertensive rats

Journal Article · Fri Jun 15 00:00:00 EDT 2018 · Biology of Sex Differences

DOI:https://doi.org/10.1186/s13293-018-0183-9· OSTI ID:1627022

Pokrzywinski, Kaytee L. ^[1]; Biel, Thomas G. ^[1]; Rosen, Elliot T. ^[1]; Bonanno, Julia L. ^[1]; Aryal, Baikuntha ^[1]; Mascia, Francesca ^[1]; Moshkelani, Delaram ^[2]; Mog, Steven ^[3]; Rao, V. Ashutosh ^[1]

---

1. US Food and Drug Administration, Silver Spring, MD (United States). Center for Drug Evaluation and Research. Office of Biotechnology Research. Division of Biotechnology review and Research III. Lab. of Applied Biochemistry
2. US Food and Drug Administration, Silver Spring, MD (United States). Center for Drug Evaluation and Research. Office of Pharmaceutical Quality. Office of Process and Facilities. Division of Process Assessment III
3. US Food and Drug Administration, College Park, MD (United States). Center for Food Safety and Applied Nurtrition

Background: Doxorubicin (DOX), an anthracycline therapeutic, is widely used to treat a variety of cancer types and known to induce cardiomyopathy in a time and dose-dependent manner. Postmenopausal and hypertensive females are two high-risk groups for developing adverse effects following DOX treatment. This may suggest that endogenous reproductive hormones can in part suppress DOX-induced cardiotoxicity. Here, we investigated if the endogenous fluctuations in 17β-estradiol (E2) and progesterone (P4) can in part suppress DOX-induced cardiomyopathy in SST-2 tumor-bearing spontaneously hypersensitive rats (SHRs) and evaluate if exogenous administration of E2 and P4 can suppress DOX-induced cardiotoxicity in tumor-bearing ovariectomized SHRs (ovaSHRs). Methods: Vaginal cytology was performed on all animals to identify the stage of the estrous cycle. Estrous-staged SHRs received a single injection of saline, DOX, dexrazoxane (DRZ), or DOX combined with DRZ. OvaSHRs were implanted with time-releasing pellets that contained a carrier matrix (control), E2, P4, Tamoxifen (Tam), and combinations of E2 with P4 and Tam. Hormone pellet-implanted ovaSHRs received a single injection of saline or DOX. Cardiac troponin I (cTnI), E2, and P4 serum concentrations were measured before and after treatment in all animals. Cardiac damage and function were further assessed by echocardiography and histopathology. Weight, tumor size, and uterine width were measured for all animals. Results: In SHRs, estrous-staged DOX treatment altered acute estrous cycling that ultimately resulted in prolonged diestrus. Twelve days after DOX administration, all SHRs had comparable endogenous circulating E2. Thirteen days after DOX treatment, SHRs treated during proestrus had decreased cardiac output and increased cTnI as compared to animals treated during estrus and diestrus. DOX-induced tumor reduction was not affected by estrous-staged treatments. In ovaSHRs, exogenous administration of E2 suppressed DOX-induced cardiotoxicity, while P4-implanted ovaSHRs were partly resistant. However, ovaSHRs treated with E2 and P4 did not have cardioprotection against DOXinduced damage. Conclusions: This study demonstrates that estrous-staged treatments can alter the extent of cardiac damage caused by DOX in female SHRs. The study also supports that exogenous E2 can suppress DOX-induced myocardial damage in ovaSHRs.

• Research Organization: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
• Sponsoring Organization: USDOE Office of Science (SC)
• Grant/Contract Number: AC05-06OR23100
• OSTI ID: 1627022
• Journal Information: Biology of Sex Differences, Vol. 9, Issue 1; ISSN 2042-6410
• Publisher: BioMed Central
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
Endocrinology & Metabolism
Genetics & Heredity
Doxorubicin
Cardioprotection
Cardiomyopathy
Estradiol
Progesterone
Adriamycin