Triggering of cell apoptosis by optical target

image: One problem with drug-based treatments is the side effects that come with them.
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Credit: (Image courtesy of Okayama University and modified by JST)

Focus on light-sensitive proteins

When performing cancer treatment, it is important to kill cancer cells. The main means of treatment are usually drugs, and many of them share the same problem: they act not only on the cancerous cells, but also on the surrounding healthy cells, causing unwanted side effects. Several light-based therapies have been developed that focus on concentrating drugs into cancer cells and then destroying them with light. In recent years, photoimmunotherapy has attracted a lot of attention. It is a revolutionary treatment that skilfully uses light as well as the host’s immune system.

“These methods use chemicals and cause physical necrosis by relying on active enzymes or heat. Thus, we cannot eliminate the adverse effects no matter how much we improve them,” emphasizes Professor Yuki Sudo, who studies biophysics at the Faculty of Medicine, Dentistry and Pharmaceutical Sciences of Okayama University. .

The means of killing cells can be broadly divided into two categories. One is necrosis, in which cells are damaged by injury, poison, or viral infection and then die. The other is apoptosis, in which unwanted cells are actively killed to allow the organism’s body to survive. “We believed that if we could stealthily induce apoptosis in target cancer cells using proteins rather than chemicals, we could help achieve a breakthrough in cancer treatment without the accompanying side effects,” explains Professor Sudo.

Professor Sudo’s research group focused on archaerhodopsin-3 (AR3), a light-activated substance found in microorganisms living in salt lakes in the United States. Such rhodopsin family proteins can absorb light and are essential for vision in vertebrates, including humans. AR3 is characterized by its ability to pump hydrogen ions out of the cell and reduce its hydrogen ion concentration. As the hydrogen ion concentration decreases, the cell becomes more alkaline and cellular alkalinization can trigger apoptosis. Based on this knowledge, the research group began testing whether cells could be made alkaline enough to induce apoptosis using AR3.

Towards a radical treatment method fundamentally different from conventional treatments

First, the researchers synthesized AR3 in human cancer-derived cells, which were then exposed to green light with a wavelength of about 550 nanometers (one nanometer equals one billionth of a meter). Cells were then alkalized by activated AR3 and most cells underwent apoptosis within approximately three hours.

Then they confirmed their approach in living beings. First, AR3 was synthesized only on sensory neurons of C.elegans, which is a commonly used laboratory animal. When exposed to green light throughout their bodies, neurons synthesizing AR3 showed a reduced sensory response to the chemicals. Hydrogen ions appeared to have been pumped out of these neurons by AR3, causing the cells to become alkalized and then die. From these results, the researchers concluded that when using AR3, light can trigger apoptosis in the targeted cells.

AR3 genes must be introduced into cells for them to synthesize AR3. This is similar to how the mRNA (messenger RNA) vaccine against COVID-19 works, in which mRNA is injected into cells to synthesize the necessary proteins. Moreover, genetic markers can be used to synthesize AR3 only in targeted cells.

“Using the ‘light-induced cell apoptosis method’ we have developed, in which AR3 is synthesized only in human cancer cells, it is possible to kill diseased cells without causing adverse reactions in surrounding healthy cells. . Some people may think that because our approach kills cancer with light, it is the same as the previous methods. However, our strategy focuses on apoptosis rather than necrosis and is therefore fundamentally different. Our approach could lead to radically new treatment methods,” remarks Professor Sudo.

In addition to Professor Sudo, the research group included Assistant Professor Keiichi Kojima, also a member of the Faculty of Medicine, Dentistry and Pharmaceutical Sciences at Okayama University. The results have been published in the online version of the Journal of the American Chemical Society February 17. This research is supported by the Strategic Basic Research Program of the Japan Science and Technology Agency (JST) and the Scientific Research Assistance Grants of the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

A remarkable achievement for a student who didn’t believe what his teacher said

The effectiveness of the proposed approach has now been confirmed in human cells and relatively simple animals used for the experiments. The next step is to carry out experiments on mammalian tissues using, for example, mice.

However, in this regard, a secret student-led experiment was key. Unbeknownst to Professor Sudo, the student conducted a parallel experiment in which the pH conditions applied to the cell were changed. pH is a measure of the concentration of hydrogen ions in an environment and is used as an index of acidity, neutrality and alkalinity. “I thought that a test of our approach could not possibly be done under neutral conditions,” says Professor Sudo, “Cells die when they are soaked in an alkaline solution and I wondered if this process could be accelerated using AR3, so I experimented only at pH 9 (alkaline), however the student also conducted an experiment at pH 7 (neutral), i.e. the conditions that normally occur in the human body.

“At neutral pH, it is necessary to observe over longer periods of time when using our approach. Despite the fact that apoptosis did not occur rapidly at neutral pH, he continued to test resolutely for another three or four hours and was finally successful. If our strategy works at neutral pH, it can be used to develop treatments. It’s wonderful that this breakthrough was made by a student who doesn’t believe what his teacher said,” says Professor Sudo.

Shin Nakao is the name of the sixth-year pharmacy student who was the driving force behind these results. “I wanted to make the conditions applicable to patients, which can’t be done at pH 9. So I tried our approach at pH 7. It worked, so I’m glad I tried,” he recalls modestly.

With the Sustainable Development Goals as key guiding principles

Professor Sudo will continue his research on rhodopsin, which is based on the concept of using light for medicine. “Light is the ultimate source of energy for all life, and we receive it every day. If light can be used for medicine, such approaches will be available in both developed and developing countries,” he says. With the UN SDGs (Sustainable Development Goals) as important indicators, Prof. Sudo’s group focuses particularly on Goal 3 “Ensure healthy lives and promote well-being for all at all ages” , the 7th goal “Ensure access to affordable services, reliable, sustainable and modern energy” and the 10th goal “Reduce inequalities within and between countries”.

It is said that Goethe, the great poet of the 18th and 19th centuries, said on his deathbed: “Mehr Licht! (More light!)” Whatever the original meaning of this phrase, it always comes to mind whenever we hear keywords related to modern technology such as renewable energy, photocatalysis and optical communications. . Human beings, including those working in the field of medicine, have many opportunities to solve the problems they face with “more light”.



(KUSAKA Takeo/Science Portal Editorial Department) The original article was provided by Science Portal and translated by Science Japan)

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