Master of Science
Pathology and Laboratory Medicine
Doxorubicin (DOX) is a powerful chemotherapy that functions by interfering with cancer cells’ growth. However, the use of DOX is limited due to its detrimental side effects that can lead to serious cardiovascular complications. Our goal is to determine if nicotinamide mononucleotide (NMN) and histone acetyltransferase (HAT) inhibitors can protect against DOX-induced cardiotoxicity. Our findings revealed that DOX reduced NAD+ concentration and induced damage to H9c2 cells as evidenced by higher caspase-3 activity and lactate dehydrogenase release. Pre-incubation with NMN increased NAD+ concentration and attenuated DOX-induced damage. There was higher cell viability in the NMN pre-incubated group compared to the vehicle treated group in response to DOX. Furthermore, mice pre-treated with NMN had higher ejection fraction and fraction shortening percentage compared to the vehicle treated group. In contrast, pre-incubation with HAT inhibitors failed to protect DOX-treated cells. Thus, our study suggests that NMN may be a potential drug that prevents DOX-induced cardiotoxicity.
Summary for Lay Audience
With about 9.8 million patients worldwide needing treatment annually, chemotherapy is a widely used treatment option for cancer patients. Doxorubicin (DOX) is a well-established chemotherapy drug that is prescribed for a diverse range of cancer types. DOX has a drawback as it causes heart damage, which is referred to as DOX-induced cardiotoxicity. In severe cases, DOX-induced cardiotoxicity can result in heart failure leading to death, even years after the patient has stopped their treatment.
The imbalance between histone deacetylase and histone acetyltransferase activity may be the main cause of DOX-induced cardiotoxicity. Histone deacetylases are enzymes that function to removes chemical molecules called acetyl groups. Previous research in our laboratory showed that nicotinamide riboside, a compound similar to Vitamin B3, protected against DOX-induced cardiotoxicity. We found that when cells take in nicotinamide riboside, it is converted into a molecule called nicotinamide adenine dinucleotide (NAD+). NAD+ will activate a group of histone deacetylase called Sirtuins to remove acetyl groups. We predict that histone acetyltransferase, which are enzymes that function to add acetyl groups are involved as well. The exact molecular mechanisms and histone acetyltransferases’ involvement in the development of DOX-induced cardiotoxicity are still not completely understood.
The goal of my research is to determine whether there are alternative compounds that can prevent DOX-induced cardiotoxicity. In the first part of my research, I determined if Nicotinamide mononucleotide (NMN) can protect against DOX using a heart cell line and mouse models. NMN is another molecule that converts into NAD+ to activate histone deacetylase. The second part of my project tests different histone acetyltransferase inhibitors to examine whether they can protect a heart cell line from DOX. The histone acetyltransferase inhibitor functions to block specific histone acetyltransferase members from activating.
The findings from the first part of my research show that NMN increased NAD+ and functions as a source of cardioprotection against DOX. The second portion of my study shows that specific histone acetyltransferase family members are not involved in DOX-induced cardiotoxicity. Hence, my research contributes to advancing current scientific knowledge in the field of DOX-induced cardiotoxicity and discovering preventive therapeutics options for millions of cancer patients.
Dang, Rebecca, "Boosting cellular NAD+ concentration with nicotinamide mononucleotide prevents Doxorubicin-induced cardiotoxicity" (2020). Electronic Thesis and Dissertation Repository. 7206.
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Available for download on Friday, September 30, 2022