Reproductive hormone levels and differential mitochondria-related oxidative gene expression as potential mechanisms for gender differences in cardiosensitivity to Doxorubicin in tumor-bearing spontaneously hypertensive rats

• Published in: Cancer chemotherapy and pharmacology Vol. 76; no. 3; pp. 447 - 459
• Main Authors: Gonzalez, Yanira, Pokrzywinski, Kaytee L., Rosen, Elliot T., Mog, Steven, Aryal, Baikuntha, Chehab, Leena M., Vijay, Vikrant, Moland, Carrie L., Desai, Varsha G., Dickey, Jennifer S., Rao, V. Ashutosh
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2015; Springer Nature B.V
• Subjects: Animals; Apoptosis - physiology; Cancer Research; Doxorubicin - pharmacology; Doxorubicin - toxicity; Female; Gene Expression - drug effects; Gonadal Steroid Hormones - metabolism; Heart Diseases - chemically induced; Heart Diseases - metabolism; Hypertension - chemically induced; Hypertension - metabolism; Male; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Medicine; Medicine & Public Health; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Models, Animal; Oncology; Original Article; Oxidative Stress - genetics; Pharmacology/Toxicology; Rats; Rats, Inbred SHR; Sex Factors; Testosterone; Adriamycin; Dexrazoxane; Gender differences; Cardiotoxicity; Doxorubicin; Estradiol; Apoptosis
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-015-2786-8

Purpose Chemotherapy with doxorubicin (Dox) causes dose-limiting cardiotoxicity. We investigated the role that gender has on cardiosensitivity to Dox treatment by evaluating reproductive hormone levels in male, castrated male (c-male), female and ovariectomized female (o-female) adult spontaneously hypertensive rats (SHRs) and expression of mitochondria-related genes in male and female adult SHRs. Methods SST-2 breast tumor-bearing SHRs were treated with saline, Dox, dexrazoxane (Drz) or both Dox and Drz and monitored for 14 days. Tumor size was used to monitor anticancer activity. Heart weight, cardiac lesion score and serum levels of cardiac troponin T (cTnT) were used to determine cardiotoxicity. Serum estradiol (E2) and testosterone were evaluated using electrochemiluminescence immunoassays. Expression of mitochondria-related genes was profiled in heart by MitoChip array analyses. Results Dox significantly reduced tumor volume (±Drz) and increased heart weight in all genders (13–30 % vs. control). Higher heart lesion scores were observed in reproductively normal animals (male 2.9, female 2.2) than in hormone-deficient animals (c-male 1.7, o-female 1.9). Lesion score and cTnT inversely correlated with hormone levels. Reduced levels of both sex hormones were observed after Dox treatment. Gene expression analyses of Dox-treated hearts showed significant differential expression of oxidative stress genes in male hearts and apoptotic genes in both male and female hearts. Conclusions Our results demonstrate that adult tumor-bearing male SHRs are more cardiosensitive to Dox than female or hormone-deficient animals. We provide evidence to suggest that reproductive hormones negatively regulate or are inhibited by Dox-induced cardiotoxicity and the selective cytotoxic mechanism likely functions through the greater activation of oxidative stress and apoptosis in male SHRs.