Abstract
This study aimed to identify the alterations of blood metabolome levels and their association with cardiac dysfunction and cardiac injury following treatment with doxorubicin and trastuzumab. Eight-week-old male Wistar rats were divided into four groups (n = 6 per group) to receive intraperitoneal injection with either: (1) 1 mL of normal saline solution (NSS) at days 0, 4, 8, 15, 22, and 29 (control group for doxorubicin); (2) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 (doxorubicin group); (3) 1 mL of NSS at days 0–6 (control group for trastuzumab); or (4) 4 mg/kg/day of trastuzumab at days 0–6 (trastuzumab group). Four days after the last injected dose, cardiac function was determined. The rats were then euthanized to collect venous blood and the heart for the quantification of 107 serum and 100 cardiac metabolomes using mass spectrometry-based targeted metabolomics. We observed strong relationships between 72 cardiac versus 61 serum metabolomes in doxorubicin and trastuzumab groups. Moreover, significant correlations between cardiac function and the cardiac injury biomarker versus 28 and 58 serum metabolomes were revealed in doxorubicin and trastuzumab-treated rats, respectively. Interestingly, the patterns of both serum and cardiac metabolome alterations differed between doxorubicin and trastuzumab groups. Our findings emphasize the potential role of the constituents of the blood metabolome as non-invasive biomarkers to assess severity and prognosis of heart failure induced by doxorubicin and trastuzumab. These findings may contribute to the development of metabolic-targeted therapy specific for cardioprotection during different phases of cancer treatment.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Funding
This study was supported by the Research Grant for New Scholars from Thailand Science Research and Innovation (RGNS 64-059: C.T.); the Royal Golden Jubilee Ph.D. program (T.K. and N.C.; N.P. and N.C.; A.A. and N.C.; B.O. and S.C.C.); a Senior Research Scholar grant from the National Research Council of Thailand (S.C.C.); the NSTDA Research Chair Grant from the National Science and Technology Development Agency Thailand (N.C.); and a Chiang Mai University Center of Excellence Award (N.C.)
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CT, SS, NC, and SCC conceptualization; CT, WN, TK, NP, AA, and BO methodology; CT, WN, TK, NP, AA, and BA investigation; CT, WN, and SS formal analysis; CT writing—original draft; NC writing—review and editing; CT visualization; NC and SCC supervision; CT, NC, and SCC project administration; CT, TK, NP, AA, BO, NC, and SCC funding acquisition.
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The experimental protocol was approved by the Laboratory Animal Center, Chiang Mai University, Chiang Mai, Thailand (approval numbers 2563/RT-0008 and 2564/RT-0008) and was conducted in accordance with the guidelines established by U.S. National Research Council 2010. Because this study was done in the animals, consent to participate was not applicable.
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Thonusin, C., Nawara, W., Khuanjing, T. et al. Blood metabolomes as non-invasive biomarkers and targets of metabolic interventions for doxorubicin and trastuzumab-induced cardiotoxicity. Arch Toxicol 97, 603–618 (2023). https://doi.org/10.1007/s00204-022-03412-0
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DOI: https://doi.org/10.1007/s00204-022-03412-0