University of Saskatchewan team develops novel compounds for safer, more effective cancer treatment

In this post, my colleague Umashankar Das and I discuss our work on producing effective, less toxic therapeutics for cancer.

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A novel class of compounds developed by a University of Saskatchewan-led research team could yield more effective and less toxic chemotherapy drugs to treat cancer.

Team leader Jonathan Dimmock, a medicinal chemistry researcher in the College of Pharmacy and Nutrition, explained their compounds work by interacting with thiols, naturally occurring chemicals that perform several roles in cells.

The approach offers advantages over existing chemotherapy drugs which target nucleic acids found in DNA.

“Many of the compounds or drugs on the market are those that interfere with nucleic acids,” Dimmock said. “These types of compounds can be very toxic and they can also cause problems of their own, like actually inducing cancer.”

Thiols offer another approach. Among their many roles are defending cells against oxidization and modulating apoptosis – the process where worn-out cells die. One of the hallmarks of cancer cells is they don’t experience apoptosis and keep dividing out of control.

Umashankar Das, a research scientist in the Department of Chemical and Biological Engineering and long-time collaborator of Dimmock, explained that cancer cells produce an excess of thiols, such as one called glutathione. Knocking down levels of these thiols reduces cancer cells’ ability to resist drugs.

“In cancer cells, glutathione expression is very high, which creates a defense mechanism,” Das said. “Any anti-cancer compound that enters the cell cannot sustain its effect.”

To address this, the team developed a two-stage attack, first knocking down thiol levels to make the cancer cells vulnerable, then hitting them again.

“Over the years, we’ve developed the theory of ‘sequential cytotoxicity,’ which simply means you give an initial attack on the cancer cell and then you give a second chemical attack,” Dimmock said. “The cancer cells are more vulnerable to the second attack than normal cells.”

Designing molecules that selectively target thiols produced by cancer cells is the focus of many years’ work by Dimmock, Das and their collaborators. In their latest study, they tested compounds against cells from nine different types of human cancer, including common types affecting blood, colon, breast, prostate, ovaries, kidneys, and lungs.

Das explained that since the compounds they’ve developed make cancer cells more sensitive to attack, they also remove resistance to standard chemotherapy drugs – a serious problem in current therapies.

“Many of our compounds are what we call ‘multi-drug resistance revertants,’ so we’re actually creating a much more sensitive cancer cell through this process,” he said.

The team’s latest work is published in the Journal of Medicinal Chemistry. Funding support was provided through the Canadian Institutes of Health Research and other agencies.

The next step is to take the work into mice models to confirm their effects in living systems. To this end, the U of S has set up a technology licensing opportunity to invite partners to help develop these promising compounds.

For more information contact:
James Shewaga
Media Relations
University of Saskatchewan

Go to the profile of Jonathan Dimmock

Jonathan Dimmock

University Professor Emeritus, University of Saskatchewan


Go to the profile of Ramaswamy Narayanan
Ramaswamy Narayanan about 4 years ago

GSH has been an attractive cancer target for over a decade. Despite this, selective inhibition of thiols has been elusive. GSH offers cancer cell protection against xenobiotics, ionizing radiations, and oxidative stress. Elevated GSH contributes to resistance to drugs and radiation. Depletion of GSH sensitizes cancer cells to chemotherapeutics and ionizing radiation. In addition to apoptosis, GSH is also involved in regulating other forms of cancer cell death, including necrosis and autophagy.
The tumor-selective killing of cancer cells shown in this report could provide a rationale for novel cancer therapeutics. It would be informative to understand the pathways such as NFkB, MAPK and JNK affected in cancer cells upon treatment and compare it with normal cells. For ex. What happens to redox-sensitive transcription factor, NF-E2 p45-related factor-2 (Nrf2) and the genes regulated by this factor? By the same token is the cell death dependent on the status of TP53 protein?
Transcriptome and proteome analysis of the treated cells could offer a handle to define the mechanism of tumor selective effect.
The chemosensitization seen with the compound means it could also be combined with other targeted therapy and not just cytotoxics.
An interesting and potentially useful study for novel cancer therapeutics.