AHA21_Alves-Souza.pdf

Introduction: Doxorubicin (DOX) and other anthracyclines comprise important anticancer drugs. However,

anthracycline treatment-related cardiotoxicity is a major clinical problem for which there are currently no

effective treatments. Low-dose carbon monoxide (CO) presents an exciting and promising approach to

preventing anthracycline cardiotoxicity. Endogenous CO is generated in the body by heme oxygenase

enzymes during the degradation of heme. There is a literature precedent that supports low-dose CO in

providing cardioprotection without reducing DOX eficacy.

Hypothesis: the present study aimed to test an oral formulation of CO (HBI-002) to attenuate DOXinduced

cardiotoxicity.

Methods: Male C57BL/6, 10 to 12-week-old mice were subjected to acute (single dose, 20mg/kg, i.p.),

and chronic (ten doses, 2mg/kg, i.p., every other day) DOX regimens in combination with HBI-002

(10ml/kg) or vehicle (10ml/kg). Animals were sacrificed after one hour of single DOX injection to evaluate

serum tissue damage markers, such as creatine kinase (CK), lactate dehydrogenase (LDH), and heme.

Moreover, cardiac function was evaluated after seven days of single DOX injection and after a chronic DOX

regimen by echocardiography.

Results: Here, we show that after DOX injection, HBI-002 can prevent a rapid and early release of excess

serum CK (Vehicle: 2547 ± 260 U/L vs. HBI-002: 1122 ± 168 U/L; p<0.05), LDH (Vehicle: 1390 ± 103 U/L

vs. HBI-002: 1122 ± 168 U/L; p<0.05), and heme (Vehicle: 47.5 ± 6.7 uM vs. HBI-002: 5.3 ± 2.7 uM;

p<0.05) levels. Moreover, we observed that HBI-002 prevented a decrease in the ejection fraction after

seven days of a single dose of DOX (Vehicle: 54.3 ± 1.3% vs. HBI-002: 64.7 ± 7.5%; p<0.05), as well as

after DOX chronic regimen (Vehicle: 44.5 ± 3.6% vs. HBI-002: 61.6 ± 5.4%; p<0.05). Finally, HBI-002

attenuated DOX-induced mortality compared to the vehicle-treated group.

Conclusions: Collectively, these findings support HBI-002 as a promising cardioprotective agent against

DOX toxicity and warrant further development as a therapeutic.