Reining in Aggressive Prostate Cancer: Nature Provides Two Promising Inhibitors

Reducing the activity of a natural enzyme that gives cancer a boost could offer a viable new treatment strategy, according to results from the LBMCC in Luxembourg.

By Abby Tabor | Science Journalist at MyScienceWork

By blocking one of cancer’s accomplices in the body, researchers from the LBMCC lab at Kirchberg Hospital (Luxembourg) were able to make prostate cancer less aggressive in experiments. They found two molecules with this ability, which have the potential to be developed into new anti-cancer drugs inspired by nature: these molecules are derived from polyvanillic acids like those found in the plant Zanthoxylum fagara.

 
Zanthoxylum fagara (Wikipedia, CC BY 2.0)

These inhibitors worked by targeting the very characteristics that allow the malignant cells to cause disease. Both molecules were able to cut down on cancer cell division and cell survival by reducing the activity of a specific enzyme that can give cancer a leg up. 

HDAC affects cellular processes related to cancer…

The Luxembourg-based LBMCC, specialized in molecular oncology, and the College of Pharmacy at South Korea’s National University of Seoul, led by Prof. Marc Diederich, were studying a certain category of enzyme involved in the development and resistance of many cancers. Called histone deacetylases (HDAC), they work on other proteins in the cell, modifying them in ways that can change their activity, maybe strengthening it or speeding it up. In this way, HDAC is able to affect whether certain genes are expressed or not, the shape and movement of the cell, its ability to divide, and more.

HDAC6 (Image: Wikipedia, Public Domain)

According to Dr. Michael Schnekenburger, head of the LBMCC team involved with this study, one particular form, HDAC6, facilitates a couple of cellular phenomena that, when uncontrolled, contribute to the aggressive nature of prostate cancer. The first involves a protein that serves as the bricks of a cell’s internal framework, the cytoskeleton. Through its effects on this protein, HDAC6 helps to build and disassemble this structure as needed, playing a role in the cell’s movement and its progression through the cell division cycle. Both of these ordinary cellular activities, when taken to extremes, are found in cancer’s bag of tricks: malignant cells multiply without control, and cancers metastasize, or spread throughout the body.

Certain prostate cancers are also hormone-sensitive and depend on the presence of the androgen receptor (AR), which is activated by hormones like testosterone. Here, too, HDAC6 plays a role: it maintains a plentiful supply of AR by preventing the receptor’s degradation, and helps it reach its destination inside the cell’s nucleus, where AR controls the expression of certain genes related to the cancer.

…so, blocking HDAC could slow down the disease. 

What all this means is that, given its involvement in cancer, blocking the activity of HDAC6 could present a new strategy to help rein in the effects of aggressive prostate cancer. The LBMCC tested two molecules that should do just that. At different doses, both inhibitors were able to cut HDAC’s activity in half. This was the case in both types of prostate cancer tested: one androgen-dependent, where inhibiting HDAC reduced the amount of AR present, and the other hormone-independent.

Specifically, the HDAC6 inhibitors, called 13a and 7b in the study, were able to reduce multiplication of the cancerous cells. The overall survival of the prostate cancer cells under study also dropped considerably. Importantly, the two molecules were good at targeting cancer cells specifically and leaving healthy cells alone.

According to Dr. Carole Seidel, first author on the study, 13a and 7b are promising starting points for the development of a new kind of prostate cancer drug. “They are interesting both for their anti-cancer activities and their unusual chemical structures. These molecules could be used as the building blocks for more potent inhibitors of HDAC6 that would reach their target more specifically, too.”


You can read the full publication on the following link: 4-Hydroxybenzoic acid derivatives as HDAC6-specific inhibitors modulating microtubular structure and HSP90α chaperone activity against prostate cancer

Reining in Aggressive Prostate Cancer: Nature Provides Two Promising Inhibitors
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