Breast cancer remains a significant challenge, particularly in aggressive forms like triple-negative breast cancer (TNBC). This is a type of breast cancer where the tumour cells lack hormonal receptors, like estrogen receptors. This means that common breast cancer treatments targeting these receptors are not effective against TNBC, making it more challenging to treat and prone to spreading. Scientists are constantly searching for new ways to target the underlying mechanisms that allow these cancer cells to grow and spread unchecked.
One promising area of research involves understanding how cancer cells control their genes. Genes contain instructions for building and running a cell. Enzymes called histone deacetylases, or HDACs, are like volume knobs for genes, involved in turning up or down the expression of specific genes. When HDACs are overactive, they can silence genes that typically help control cell growth or trigger cell death, essentially turning down the volume on important instructions that keep cells healthy.
Researchers have been developing molecules that can block or inhibit these overactive HDACs. However, there are many different types, or isoforms, of HDACs in the body, and existing inhibitors often block several types at once, leading to unwanted side effects.
To address this, new research from Birla Institute of Technology and Science-Pilani, Hyderabad, Jadavpur University, and The Neotia University focused on designing new molecules that target a specific HDAC called HDAC3. HDAC3 is known to play a key role in the development and spread of aggressive breast cancer like TNBC.
The researchers designed a series of new molecules based on an organic compound– benzamide- known to interact with HDACs. They introduced a modification by adding chirality to the molecule's structure. Chirality or handedness, refers to the property of asymmetry where an object cannot be superimposed on its mirror image. Adding this handedness, or chirality, can change how a molecule interacts with its biological targets, potentially making it more selective.
After designing and creating these new molecules in the lab, the researchers tested them. They first checked how well the molecules inhibited different types of HDAC enzymes. They found that one molecule in particular, compound 7c synthesised from a compound 4-acetylpyridine, was particularly good at blocking HDAC3. It was about 47 times more potent against HDAC3 than against HDAC2 and even more selective than other HDAC types.
This was a significant improvement over some existing inhibitors that block multiple HDACs. Next, they tested how well these molecules could kill cancer cells in the lab, using several different human and mouse breast cancer cell lines, including one for TNBC. Compound 7c effectively killed these cancer cells, even at relatively low concentrations. Importantly, it was much less toxic to normal, healthy cells, suggesting it might have fewer side effects than less selective drugs.
To understand how compound 7c was killing cancer cells, they looked closer at the TNBC cells treated with it. They found that 7c caused the cancer cells to stop dividing at a specific point in their growth cycle, called G2/M arrest, and triggered apoptosis, which is essentially programmed cell suicide. They also saw an increase in reactive oxygen species (ROS) within the cancer cells. ROS are unstable molecules that can damage cells and contribute to cell death, which builds up inside the cancer cells when treated with 7c.
Mice treated with compound 7c showed significantly reduced tumour growth compared to untreated mice or mice treated with a reference inhibitor (CI994). Compound 7c also dramatically reduced the spread of the cancer to the lungs, a common site for metastasis in breast cancer. The mice treated with 7c maintained their body weight and showed no signs of significant organ damage, suggesting the molecule was well-tolerated at the tested doses. Further tests on the tumour tissue confirmed that 7c increased apoptosis and decreased cell division and metastasis, aligning with the lab results.
The researchers also used computer simulations to understand how compound 7c interacts with the HDAC3 enzyme. They found that the molecule fits snugly into the active site of HDAC3, like a key in a lock, forming strong and stable connections. The chirality they introduced played a role in this specific binding and the molecule's selectivity for HDAC3 over other HDAC types.
This research could be a significant step forward in the search for new breast cancer treatments. By designing a molecule that explicitly targets HDAC3 without causing substantial toxicity, the scientists have identified a strong candidate for further development. While more research and clinical trials are needed, compound 7c offers hope for a potential new therapeutic option for patients battling aggressive breast cancer and offers a more targeted and effective way to reduce cancer growth.This research article was written with the help of generative AI and edited by an editor at Research Matters.
This research article was written with the help of generative AI and edited by an editor at Research Matters.