This paper shared on twitter by some prominent CardioOncologists might be of interest to some as it discusses doxorubicin induced cardiotoxicity & looking at mechanisms through genomic analysis. Sounds like it’s right up @Davisite alley!
Understanding these MOA is probably an important part as to why Bisantrene is cardio protective, and looking forward to RAC releasing the paper on Bisantrene MOA.
Abstract paper:
https://www.jacc.org/doi/10.1016/j.jaccao.2023.11.008
PDF version:
https://www.jacc.org/doi/epdf/10.1016/j.jaccao.2023.11.008
ANALYSIS & SUMMARY BY GPT
Analysis of Doxorubicin's Role in Cardiovascular Toxicity and Summary of Its Effects
Doxorubicin-Induced Cardiotoxicity (DIC): Doxorubicin is a widely used anthracycline in cancer treatment, but it is associated with significant cardiotoxicity. The cardiotoxic effects of doxorubicin are primarily dose-dependent and can manifest in about 9% of patients, with most cases appearing within the first year of treatment.
Mechanisms of Cardiovascular Toxicity: The paper identifies four key molecular mechanisms through which doxorubicin induces cardiotoxicity:
Generation of Reactive Oxygen Species (ROS):Doxorubicin induces the production of ROS, particularly within the mitochondria, leading to oxidative stress and damage to cardiomyocytes. This is a major contributor to DIC, as confirmed by the functional validation of genes involved in ROS production and handling.Mitochondrial Dysfunction:Mitochondrial dysfunction is a critical aspect of DIC, where the mitochondrial DNA and membrane integrity are compromised, leading to impaired energy production and increased ROS generation.DNA Damage:Doxorubicin causes DNA damage by intercalating into DNA strands and disrupting the function of topoisomerase II beta (TOP2B), an enzyme critical for DNA repair. This damage triggers cell death pathways in cardiomyocytes.Calcium Overload:Doxorubicin also disrupts calcium homeostasis in cardiomyocytes by enhancing the activity of L-type calcium channels and binding to ryanodine receptors, which leads to excessive calcium release from the sarcoplasmic reticulum. This calcium overload contributes to sarcomere damage and impaired cardiac contractility.Functional Validation of Genes Related to DIC: The study conducted functional validation of 38 genes associated with anthracycline-induced cardiotoxicity (AIC) using CRISPR/Cas9 gene knockout in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The results provided insights into the roles of various genes in the development of DIC:
Protective Genes:Knockouts of uptake transporters (e.g., SLC28A3, SLC22A17, SLC28A1) were found to be protective against DIC by reducing the intracellular uptake of doxorubicin, thereby lowering cardiomyocyte exposure to the drug.Genes Increasing Susceptibility to DIC:Knockouts of several efflux transporters (e.g., ABCC10, ABCC2, ABCB4, ABCC5, ABCC9) increased susceptibility to DIC by allowing higher intracellular concentrations of doxorubicin.Other genes linked to ROS handling (e.g., CBR1, CBR3, RAC2), DNA damage (e.g., PRDM2, MLH1), and calcium handling (e.g., MYH7, CELF4) were also associated with increased DIC when knocked out, highlighting their protective roles.
Summary: The study establishes that doxorubicin-induced cardiotoxicity results from complex interactions between various genetic factors that affect ROS production, DNA repair mechanisms, iron uptake, and calcium handling in cardiomyocytes. These findings underscore the importance of understanding the genetic predispositions to DIC for developing targeted cardioprotective therapies and improving patient outcomes.
I have also run a query about Bisantrene & doxorubicin synergy but will post in the GPT threads later.
interesting to see the 4 main ways that Dox leads to cardiotoxicity, from iron, calcium overloads, mitochondrial & DNA aspects. Love to see if this adds to discussion about how we will lead to better cancer treatment and best in class assets.
(20min delay)