AR3-based optogenetic strategy shows high efficacy in inducing apoptosis and antitumor effects

AR3-based optogenetic strategy shows high efficacy in inducing apoptosis and antitumor effects

One of the hallmarks of cancer cells is their ability to escape apoptosis, programmed cell death, through changes in protein expression. Inducing apoptosis in cancer cells has become a major focus of novel cancer therapies because these approaches may be less toxic to healthy tissue than traditional chemotherapy or radiation. Many chemical agents are currently being tested for their ability to trigger apoptosis, and researchers are increasingly exploring light-activated molecules that can be targeted using lasers to tumor sites without sparing surrounding healthy tissue.

Cancer cells have mitochondria, which provide energy for rapid growth and division. However, it is believed that an environment that is too alkaline disrupts the function of mitochondria and leads to apoptosis.

A microbial protein called archaerhodopsin-3 (AR3) may be key to alkalinity-induced apoptosis. When exposed to green light, AR3 pumps hydrogen ions out of the cell, increasing alkalinity, disrupting cell functions, and ultimately triggering apoptosis. The ability of AR3 to induce apoptosis in cancer-specific cell lines was highlighted in a recent article by Professor Yuki Sudo, Dr. Keiichi Kojima, Dr. Shin Nakao and her team from the Graduate School of Medicine, Dentistry and Pharmaceutical Sciences at Okayama University, Japan. Their results were published online inJournal of the American Chemical Societyon November 4, 2025.

“In our previous study, we established a novel optogenetic method to induce apoptotic cell death through intracellular pH alkalinization with AR3.”said Prof. Sudo. He added:“In this study, we applied our AR3-based optogenetic strategy to murine cancer cell lines and demonstrated its high efficacy in inducing apoptosis and antitumor effects both in vitro and in vivo.”

The authors first used genetically engineered viruses to insert AR3 genes into a mouse colon cancer cell line (MC38) and a melanoma cell line (B16F10). Cells without AR3 expression survived normally when exposed to green light. In contrast, AR3-expressing cells showed high cell death rates – over 40% for MC38 and over 60% for B16F10 – as well as clear signs of mitochondrial disruption as a cause of apoptosis. In the absence of green light, no apoptosis occurred, confirming that AR3 activity was specifically induced by light.

Encouraged by these findings, the team used these cell lines to induce tumor formation in healthy mice. When these tumors were exposed to green laser light six days later, AR3-expressing tumors showed significant cell death and reduced cell proliferation in the outer layers of the tumor. More importantly, AR3-expressing tumors were 65 to 75% smaller than non-AR3 tumors 13 days after tumor implantation.

“Notably, in tumors derived from MC38 cells, a reduction in tumor volume was observed between days 10 and 13 after cell transplantation. This delayed regression may reflect not only the direct effects of apoptosis induction and inhibition of cell proliferation, but also the activation of antitumor immune responses.adds Prof. Sudo.

Although these results are very promising, the study used genetically modified cancer cells before implantation and further research is needed to determine whether pre-existing tumors can be made to express AR3 effectively. The authors also note that light penetration remains a limitation, as green laser light can only induce apoptosis to a depth of approximately 1 mm.

“By demonstrating light-induced apoptosis and significant suppression of tumor growth in two different cancer models, MC38 and B16F10, we highlight the generalizability and effectiveness of this approach.”said Prof. Sudo, emphasizing the importance of these results. The authors suggest that AR3-based optogenetic therapy could eventually be combined with other cancer treatments to increase efficacy and target a broader range of tumors.

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