Department of Surgery Beth Israel Deaconess Medical Center, Harvard Medical School Boston MA USA.
Department of Biology and Marine Biology University of North Carolina Wilmington Wilmington NC USA.
J Am Heart Assoc. 2024 May 7;13(9):e032067. doi: 10.1161/JAHA.123.032067. Epub 2024 May 3.
Doxorubicin and other anthracyclines are crucial cancer treatment drugs. However, they are associated with significant cardiotoxicity, severely affecting patient care and limiting dosage and usage. Previous studies have shown that low carbon monoxide (CO) concentrations protect against doxorubicin toxicity. However, traditional methods of CO delivery pose complex challenges for daily administration, such as dosing and toxicity. To address these challenges, we developed a novel oral liquid drug product containing CO (HBI-002) that can be easily self-administered by patients with cancer undergoing doxorubicin treatment, resulting in CO being delivered through the upper gastrointestinal tract.
HBI-002 was tested in a murine model of doxorubicin cardiotoxicity in the presence and absence of lung or breast cancer. The mice received HBI-002 twice daily before doxorubicin administration and experienced increased carboxyhemoglobin levels from a baseline of ≈1% to 7%. Heart tissue from mice treated with HBI-002 had a 6.3-fold increase in CO concentrations and higher expression of the cytoprotective enzyme heme oxygenase-1 compared with placebo control. In both acute and chronic doxorubicin toxicity scenarios, HBI-002 protected the heart from cardiotoxic effects, including limiting tissue damage and cardiac dysfunction and improving survival. In addition, HBI-002 did not compromise the efficacy of doxorubicin in reducing tumor volume, but rather enhanced the sensitivity of breast 4T1 cancer cells to doxorubicin while simultaneously protecting cardiac function.
These findings strongly support using HBI-002 as a cardioprotective agent that maintains the therapeutic benefits of doxorubicin cancer treatment while mitigating cardiac damage.
多柔比星和其他蒽环类药物是癌症治疗的重要药物。然而，它们与显著的心脏毒性相关，严重影响了患者的护理，并限制了剂量和使用。先前的研究表明，低一氧化碳（CO）浓度可预防多柔比星毒性。然而，传统的 CO 输送方法在日常给药方面存在复杂的挑战，如剂量和毒性。为了解决这些挑战，我们开发了一种新型的含有 CO 的口服液体药物产品（HBI-002），正在接受多柔比星治疗的癌症患者可以方便地自行使用，从而通过上消化道输送 CO。
在存在和不存在肺癌或乳腺癌的情况下，在多柔比星心脏毒性的小鼠模型中测试了 HBI-002。小鼠在接受多柔比星前每天接受两次 HBI-002 治疗，从基线的约 1%增加到 7%的羧基血红蛋白水平。与安慰剂对照组相比，用 HBI-002 治疗的小鼠心脏组织中的 CO 浓度增加了 6.3 倍，并且保护性酶血红素加氧酶-1 的表达更高。在急性和慢性多柔比星毒性情况下，HBI-002 均能保护心脏免受心脏毒性作用，包括限制组织损伤和心脏功能障碍以及提高存活率。此外，HBI-002 并未降低多柔比星减少肿瘤体积的功效，而是增强了乳腺癌 4T1 细胞对多柔比星的敏感性，同时保护了心脏功能。
这些发现有力地支持使用 HBI-002 作为心脏保护剂，在保持多柔比星癌症治疗的治疗益处的同时减轻心脏损伤。
