Anthracycline Cardiotoxicity and FTO overexpression
Anthracyclines (ANTs) exert their anti cancer action by directly targeting and inhibiting topoisomerase 2 (Top2) in cancer cells, more specifically the 2a isoform, halting DNA transcription, and replication.
The evidence suggests that this mechanism cannot explain the toxic effect of ANTs on the heart, since cardiomyocytes are non-dividing cells. Recent evidence suggests that doxorubicin (DOX) cardiotoxicity is causally linked to inhibition of a Top2 isoform which is preferentially expressed by differentiated cells, like cardiomyocytes, namely Top2b, the only Top2 expressed in mitochondria (1,2).
While this is the case, a number of other mechanisms of anthracycline-induced cardiotoxicity (AIC) which are not linked to Trop2b inhibition have started to emerge that also influence the activity of mitochondria in cardiomyocytes. These mechanisms can be described as Trop2 dependent and independent mechanisms of AIC. The data that discusses these mechanisms is very long and complex with lots of jargon, so I have decided to share a very quick summary of molecules influenced by doxorubicin or anthracycline treatment (below). The article I have cited is a summary paper and includes all of the individual studies I have gathered this data from.
Briefly, anthracyline treatment alters mitochondria structure, metabolism, and biogenesis, produces free radicals that damage cells, negatively influences calcium homeostasis, and inhibits autophagy (a positive and necessary cellular repair mechanism).
I've also put together some of the evidence that I have found for the influence of FTO inhibition on these processes (assumed in some cases). Remember the expression of these molecules are seen when you inhibit FTO.
To compare anthracycline/doxorubicin treatment to that of FTO inhibition specifically, you can start to appreciate some interesting differences between the two.
What you will see is that FTO inhibition has the opposite effect in genes that regulate autophagy and ROS generation. What this means is that autophagy (a healthy, natural, and positive cellular process) is upregulated when FTO is inhibited. This allows for a cleaning up of the cellular environment. Also, ROS production is increased with FTO overexpression, suggesting that inhibition of FTO may lead to a reduction in ROS production, which would decrease the cellular damage done by these molecules. Some of the 'same' expression factors found include expression of PGC-1a which influences mitochondrial biogenesis and SERCA2 and RyR2 which modify calcium homeostasis.
This evidence gives me confidence in the heart safety confered by historic trials was primarily a result of FTO inhibition - the mechanism is entirely plausible. I also suspect that this may be the very early confirmation of circumstantial evidence supporting the notion that bisantrene could inhibit FTO in normal cells and modify the cellular environment. Based on the evidence presented here and the City of Hope paper demonstrating the high selectivity of bisantrene to bind to the catalytic pocket of FTO, the theory that bisantrene's cardiac safety is a result of being a poor anthracene-like drug is less conclusive for me.
Hence, I suspect that mainly FTO inhibition and possibly poor anthracene-like qualities are in-part responsible for the cardiac safety seen.
1 https://pubmed.ncbi.nlm.nih.gov/1380833/
2 https://pubmed.ncbi.nlm.nih.gov/23104132/
- Forums
- ASX - By Stock
- RAC
- Pillar 2 - Breast Cancer
Pillar 2 - Breast Cancer, page-125
-
- There are more pages in this discussion • 5 more messages in this thread...
You’re viewing a single post only. To view the entire thread just sign in or Join Now (FREE)
Featured News
Add RAC (ASX) to my watchlist
|
|||||
Last
$1.66 |
Change
-0.020(1.19%) |
Mkt cap ! $282.8M |
Open | High | Low | Value | Volume |
$1.68 | $1.68 | $1.61 | $118.5K | 72.33K |
Buyers (Bids)
No. | Vol. | Price($) |
---|---|---|
1 | 500 | $1.65 |
Sellers (Offers)
Price($) | Vol. | No. |
---|---|---|
$1.66 | 601 | 1 |
View Market Depth
No. | Vol. | Price($) |
---|---|---|
1 | 500 | 1.650 |
1 | 276 | 1.630 |
1 | 2000 | 1.625 |
2 | 1025 | 1.620 |
1 | 3000 | 1.615 |
Price($) | Vol. | No. |
---|---|---|
1.660 | 601 | 1 |
1.700 | 6382 | 1 |
1.720 | 580 | 1 |
1.730 | 309 | 1 |
1.735 | 609 | 1 |
Last trade - 16.10pm 04/09/2024 (20 minute delay) ? |
Featured News
RAC (ASX) Chart |