Chat GPT Q&A, page-394

Im finding the level of detail in using Perplexity over ChatGPT to be far superior. It even provides the infographics.
I think Perplexity is actually searching scientific studies vs GPT seems to just look for the info on websites that are publicly available.

Q. What is the MOA of Bisantrene?
Bisantrene (C₂₂H₂₂N₈) is an anthracene-derived antineoplastic agent with a dual mechanism of action (MOA) combining DNA disruption and epigenetic modulation.

Primary MOA: DNA Intercalation and DamageBisantrene intercalates into DNA, inducing structural disruptions that lead to single-strand breaks and DNA-protein crosslinks, effectively blocking DNA replication. This mechanism is similar to anthracyclines like doxorubicin but with significantly reduced cardiotoxicity. Unlike anthracyclines, bisantrene does not generate reactive oxygen species (ROS), contributing to its safer cardiac profile.

Secondary MOA: FTO InhibitionBisantrene selectively inhibits the Fat Mass and Obesity-associated protein (FTO), an m⁶A RNA demethylase, at nanomolar potency (IC₅₀ = 142 nM). By suppressing FTO, bisantrene alters RNA methylation patterns, disrupting leukemia stem cell self-renewal and enhancing cytotoxicity in acute myeloid leukemia (AML). This epigenetic effect complements its DNA-targeted activity, particularly in resistant or relapsed cancers.

Clinical Implications
• Reduced cardiotoxicity: Bisantrene’s lack of ROS generation and cardioprotective properties make it suitable for combination therapies with anthracyclines.
• Efficacy in AML: Phase II trials show a 40% overall response rate in relapsed/refractory AML, with minimal cardiotoxicity.In summary, bisantrene’s MOA combines direct DNA damage and epigenetic regulation, offering a unique therapeutic profile in oncology.

Q. What specific molecular changes occur in cardiomyocytes when bisantrene is administered with anthracyclines?

When bisantrene is administered with anthracyclines, several specific molecular changes occur in cardiomyocytes that can alter the typical pattern of cardiotoxicity seen with anthracyclines alone:

• Reduction in Reactive Oxygen Species (ROS) Generation: Anthracyclines like doxorubicin induce cardiotoxicity primarily through excessive ROS production, leading to mitochondrial damage, membrane lipid peroxidation, and cell death. Bisantrene, in contrast, does not generate significant ROS, so its presence can reduce the overall oxidative stress burden in cardiomyocytes when combined with anthracyclines.
• Mitochondrial Protection: Anthracyclines disrupt mitochondrial membrane potential, open the mitochondrial permeability transition pore (MPTP), and trigger the release of cytochrome c, leading to apoptosis. Bisantrene’s lack of ROS production and distinct DNA interaction profile may help preserve mitochondrial integrity, reducing MPTP opening and cytochrome c release, thereby preventing apoptosis in heart cells.
• Calcium Homeostasis: Anthracyclines cause calcium overload in cardiomyocytes by disrupting sarcoplasmic reticulum function, which contributes to mitochondrial injury and cell death. By not exacerbating ROS or calcium dysregulation, bisantrene may help maintain more stable calcium handling in the presence of anthracyclines.
• Reduced Activation of Matrix Metalloproteinases (MMPs): Anthracyclines activate MMP2, leading to degradation of contractile proteins and extracellular matrix remodeling, which impairs cardiac function. Bisantrene’s lower oxidative stress profile may limit this MMP activation, preserving cardiac structure.
• DNA Damage Pathways: Both drugs can intercalate DNA and inhibit topoisomerase II, but bisantrene’s distinct molecular structure and lack of ROS generation mean it does not amplify the DNA damage and apoptotic signaling in cardiomyocytes to the same extent as anthracyclines.In summary:When combined with anthracyclines, bisantrene can mitigate several key molecular triggers of cardiomyocyte injury-especially ROS-driven mitochondrial damage, calcium overload, and contractile protein degradation-resulting in a cardioprotective effect even as both drugs retain anticancer activity.