Research Article published 6 May 2023:
Induction of endoplasmic reticulum stress is associated with the anti-tumor activity of monepantel across cancer types
https://onlinelibrary.wiley.com/doi/10.1002/cam4.6021
(great find, Paralogical)
This paper has been years in the making and is the culmination of critical, multi-disciplinary research lead from the world recognised Olivia Newton-John Cancer Research Institute.
This will underpin the direction of PharmAust into the future in relation to the treatment of a broad range of cancers in humans.
Some Key contributors: - Roger Aston (PharmAust)
- Richard Molard (PharmAust) - roles included funding acquisition!!!
- Walter Douglas Fairlie (Olivia Newton-John Cancer Research Institute) - LEAD
- Includes interactions with WEHI & multiple research grants (note funding via PharmAust)
At first glance, it is somewhat overwhelming with scientific jargon and this is very difficult to consume.
So here is a more simplistic version of the Abstract. I am also offering some definitions for some of the terms that I don't hear used in common language too. What I can't do is understate the importance of this published works. IT clearly articulates the viability and validity of the PharmAust held IP and vision held for Monepantel.
Some key terms first: ATF4-mediated ER stress responses - involve activating genes for protein folding, amino acid metabolism, antioxidant defence, apoptosis, and autophagy to cope with endoplasmic reticulum stress. (ok, now read the rest of the definitions and come back to this one!)
Apoptosis - cell death
Autophagy - a process that helps cells break down and recycle their components
EndoplasmicReticulum (ER) - a cellular structure involved in protein synthesis
ER stress responses - the cellular reactions triggered when the endoplasmic reticulum (ER), a specialised organelle (a sub-cellular structure that has one or more specific jobs to perform in the cell) involved in protein synthesis and folding, becomes overwhelmed or disrupted. The ER plays a crucial role in ensuring that newly synthesised proteins are correctly folded and processed before they are transported to their functional destinations within the cell.
mTOR (mechanistic target of rapamycin) - a protein kinase that plays a central role in regulating cell growth, metabolism, and survival. It acts as a key regulator of various cellular processes in response to nutrient availability, growth factors, and energy status.
Pro‐apoptotic proteins - initiate apoptosis by blocking the anti‐apoptotic activity of Bcl‐2 and Bcl‐xL by binding to their mitochondrial binding sites or by triggering the activation of pro‐apoptotic Bax/Bak.
RNA-sequencing - a technique that allows them to analyse gene activity
Western blotting -also known as immunoblotting, is a widely used laboratory technique for detecting and analysing specific proteins in a sample of biological material.
3D cultures - cultures refer to a method of growing cells in the laboratory that better mimics the natural environment of cells in the body. In traditional cell culture, cells are typically grown in a flat, two-dimensional (2D) layer on a plastic dish or flask. However, this does not fully replicate the complex three-dimensional structure and interactions between cells that occur in tissues and organs.
Now, Abstract (with less jargon):
Monepantel is a drug that can kill parasitic worms and also has the ability to fight against cancer. Scientists have been studying this drug for a while, but they still don't know exactly how it works in human cells. However, they have some clues about its effects on cell processes like the cell cycle (the process of cell growth and division), mTOR signaling (a pathway that regulates cell growth and metabolism), and autophagy (a process that helps cells break down and recycle their components).
To understand how monepantel affects cancer cells, the researchers conducted experiments using more than 20 different types of solid cancer cells. They tested the drug's ability to reduce cell viability (how well t
he cells can survive) and induce apoptosis (cell death) in a subset of these cells, including cells grown in 3D cultures. They also used genetic techniques to delete specific genes involved in apoptosis and autophagy to see how these processes contribute to the drug's effectiveness. Additionally, they performed RNA-sequencing, a technique that allows them to analyze gene activity, on four cell lines treated with monepantel, and confirmed the changes in gene expression using a method called Western blotting.The results of their experiments showed that monepantel can slow down the growth of a wide range of cancer cells. In some cases, it induced apoptosis, which they confirmed by using cells that lacked certain genes involved in apoptosis. However, even in cells where apoptosis was blocked, the drug still inhibited cell growth, indicating that it affects the cell cycle as the main way to fight cancer.
Previous studies have suggested that autophagy, another cell process, may also contribute to cell death caused by monepantel. The researchers observed autophagy induction in multiple cell lines, but when they deleted a key gene involved in autophagy, called ATG7, they found that it had minimal impact on the drug's ability to slow down cell growth.
This suggests that autophagy might be associated with the drug's effects on cancer cells, but it is not necessary for its anti-tumor activity.Further analysis of the genes in the treated cells revealed that monepantel downregulated many genes involved in the cell cycle, while upregulating genes related to a stress response in the endoplasmic reticulum (a cellular structure involved in protein synthesis). These changes were particularly associated with ATF4-mediated ER stress responses, especially genes involved in amino acid metabolism and protein synthesis.
In conclusion, based on their findings, the researchers propose that monepantel's anti-cancer activity is likely triggered by its effects on mTOR signaling, the cell cycle, and autophagy. The drug seems to disrupt the cell cycle and induce apoptosis in some cases, while autophagy may be associated with its anti-tumor effects but not necessarily required. The changes in gene expression observed suggest that monepantel affects various cellular processes related to cell growth and metabolism, providing insights into its mechanisms of action against cancer cells.
Now for a KICKER of a diagram:
Let's select a few to review:
Top, Left > No big impact on healthy cells!
Top, Middle > Again, no big impact on healthy cells
Top, Left > BOOM - absolutely huge response to MELANOMA
Middle, middle > another BOOM with OVARIAN CANCER
Lower, Left > saving the biggest BOOM for something that is incredibly hard to treat, BRAIN CANCER
NOTE: The blood/brain barrier work underway with MND is vital to brain cancer analysis.
Others are also exciting but these are my top liners above.
To say this is both exciting and affirmation of my long held belief is an understatement. Thank you to the researcher and to PharmAust for enabling this research & obtaining the grants to make it as broad and enlightening.
adreamer
(20min delay)
