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Vol 24, No. 01, January 2020   |   Issue PDF view/purchase
COLUMNS
The Lab Report
Researchers from National University of Singapore looking to discover novel metal-based anticancer drugs with reduced toxicity.

Metal-based anti-cancer drugs have been used in cancer therapies since its first approval by the USA Food and Drug Administration in 1978. The well-known and widely used platinum-based drug – cisplatin – was discovered by Barnett Rosenberg and his team at Michigan State University in 1965.1 Despite its known anti-tumour capabilities through multiple mechanisms cisplatin is also infamous for its toxic side effects. The cytotoxic effect stems from cisplatin’s interaction with DNA and the formation of covalent bonds with purine DNA bases.2 Some forms of toxicity include nephrotoxicity, hepatotoxicity, and cardiotoxicity. Another side effect of cisplatin is nausea which can cause patients who are undergoing chemotherapy with cisplatin to vomit sometimes as many as 12 times a day.

Soon after, other less toxic metal-based anti-cancer drugs began to surface, for example, carboplatin which has shown to be significantly less neurotoxic and without nephrotoxicity while still ensuring same level of anti-cancer activity.

An emerging alternative to cisplatin are ruthenium-based anticancer drugs. Ruthenium was first discovered in Russia is within the same group as iron in the periodic table. For a long time, it has been thought that it can mimic the properties of iron in binding to proteins such as transferrin thereby acting as a ‘Trojan Horse’. Much like iron, ruthenium has been found to bind to protein, one of which is human serum albumin. This protein is an abundant intracellular protein that provides ruthenium complexes with a way to induce apoptosis in tumour cells.3 An advantage that ruthenium has over other metal-based drugs and other purely organic drugs is their structural diversity and the number of different oxidation states. Consequently, the ease of fine-tuning of the ruthenium structure based on required properties and the ability of ruthenium complexes to induce reactive oxygen species as a result of intracellular redox properties makes it a viable candidate for anti-cancer drugs.4

In 2009, a Ph.D. student of Associate Professor Ang Wee Han at the National University of Singapore (NUS), Mun Juinn Chow discovered the three-component system which allowed the in-situ synthesis of thousands of ruthenium complexes by a combinatorial approach. He then realized that this class of compounds has high potential as anti-cancer agents due to their ability to kill cancer cells and ease of synthesis and high-throughput screening.

Later with the interest of Dr. Maria Babak in cancer stem cells and the stem cell theory of cancer their laboratory set out to work on developing compounds for ruthenium-based anti-cancer drugs targeting Triple-negative Breast Cancer stem cells.

The Stem Cell Theory of Cancer

Stem cells are cell in the body that have only two functions, first is to proliferate producing similar cells and second is to differentiate into any type of cells in the body. Concepts that cancers come about from stem cells first emerged in the 19th century and was presented by Durante and Conheim as the embryonal theory of cancer.5 The theory of cancer stem cells states that there are stem cells present in heterogenous tumours which are hidden and almost impossible to detect them making them difficult to be treated.

According to the theory, after a cancer patient is treated for a tumour whether through surgery, radiotherapy, or chemotherapy, the bulk of tumour is removed. However, there is a minute number of cells still remaining which are dormant cancer stem cells that are unaffected by the treatment. These stem cells will pose a threat of tumour recurrence due to its regenerative and ability to transform into other cells. It takes less than 10 cancer cells in the body to initiate a new tumour. The time it takes to develop could explain why patients return with secondary tumours which are more aggressive several years after their first cancer. Research in recent years has drawn more evidence to demonstrate a small portion of cells in tumours being responsible for tumour initiation, proliferation, and recurrence.

Triple-Negative Breast Cancer

An aggressive subtype of breast cancer known as Triple-Negative Breast Cancer (TNBC) is characterized by the absence of oestrogen and progesterone receptors as well as the absence of Human Epidermal Receptor 2 (HER2) overexpression. This makes challenging to treat as it would not be sensitive to conventional hormone therapy like other hormone-dependent forms of breast cancer.

While studies are ongoing to develop a specific treatment or produce therapy options for TNBC, there are currently no approved targeted therapies for one of the most aggressive forms of breast cancer. Research on TNBC has also demonstrated its capabilities in recurrence and low survival rates. Many of which identified the need for new and effective targeted therapies for TNBC.

With their aims to fill this unmet clinical need, the NUS research team began working on developing compounds for ruthenium-based anticancer drugs to target breast cancer stem cells for TNBC treatment.

Developing Rutin

In a study published by Gupta et. Al.,6 high-throughput screening of a library of compounds was conducted to identify specific compounds which had targeted cytotoxicity for cancer stem cells.

Inspired by the work of those researchers, Dr Maria Babak and A/Prof Ang then started screening the three-component library which they called the Rutin library against breast cancer stem cells with the aim of targeting breast cancer metastases. Following the screening, the researchers identified the main compounds and synthesized them in large quantity. The mechanism of action and identified if their new compound is able to stop the cell renewal potential of breast cancer stem cells.

From the initial test, the new drug not only destroyed existing subpopulations of breast cancer stem cells but also stopped the ability of those few surviving breast cancer stem cells to self-renew. Motivated by the results they then tested the effect in mice models with implanted human breast cancer cells in their mammary fat pads. This work was in collaboration with the National Cancer Centre Singapore also showed a significant shrinkage in the tumours.

The toxicity of their novel drug was also tested on normal liver and heart as hepatotoxicity and cardiotoxicity are fatal side effects of cisplatin.

After their work on Rutin in breast cancer, the team also tested it on liver cancer which also showed decrease in metastasis. Further, they will be continuing on to metastatic pancreatic cancer where there is unmet clinical need. Their research will also continue to identify the target of Rutin.

References

  1. Hoeschele JD. (2014) Biography of professor barnett rosenberg: a tribute to his life and his achievements. Anticancer Res. 2014 Jan;34(1):417-21.
  2. Dasari, S., & Tchounwou, P. B. (2014). Cisplatin in cancer therapy: molecular mechanisms of action. European journal of pharmacology, 740, 364–378. doi:10.1016/j.ejphar.2014.07.025
  3. Liu, Y., Yu, Q., Wang, C., Sun, D., Huang, Y., Zhou, Y., & Liu, J. (2012). Ruthenium (II) complexes binding to human serum albumin and inducing apoptosis of tumor cells. Inorganic Chemistry Communications, 24, 104–109. doi: 10.1016/j.inoche.2012.08.009
  4. E. Orlowska, M. V. Babak, O. Dömötör, E. A. Enyedy, P. Rapta, M. Zalibera, L. Bučlinský, M. Malček, C. Govind, V. Karunakaran, Y. C. S. Farid, T. E. McDonnell, D. Luneau, D. Schaniel, W. H. Ang, and V. A. Arion, NO Releasing and Anticancer Properties of Octahedral Ruthenium− Nitrosyl Complexes with Equatorial 1H-Indazole Ligands, Inorg. Chem., 2018, 57, 10702-10717
  5. Sell S. (2010). On the stem cell origin of cancer. The American journal of pathology, 176(6), 2584–2494. doi:10.2353/ajpath.2010.091064
  6. Gupta, P. B., Onder, T. T., Jiang, G., Tao, K., Kuperwasser, C., Weinberg, R. A., & Lander, E. S. (2009). Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 138(4), 645–659. doi:10.1016/j.cell.2009.06.034

About the Researchers

Dr Maria Babak, Postdoctoral Researcher, Laboratory of Bioinorganic Chemistry, National University of Singapore

Associate Professor Ang Wee Han, Deputy Head of Department, Department of Chemistry, National University of Singapore

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