Discovery of novel anti-cancer mechanism using mitochondrial enzyme inhibitors

December 8, 2021

Possibility of new cancer treatment using the characteristics of tumor tissue

In the Project for Cancer Research and Therapeutic Evolution (P-CREATE) of the Japan Agency for Medical Research and Development, Institute of Microbial Chemistry, Japanese Foundation for Cancer Research, and RIKEN CSRS elucidated a novel anti-cancer mechanism via acidification of the tumor environment by mitochondrial respiratory chain complex I inhibitors.

Respiratory chain complex I inhibitors have been expected to exert their anticancer effects by inhibiting the energy metabolism of cancer cells, thereby depleting ATP, the energy source of cancer cells. However, as the metabolic pathways responsible for the production of ATP are altered in various ways in cancer cells, respiratory chain complex I inhibitors have not always yielded good results in the development of anticancer drugs using energy depletion as an indicator.

In the process of analyzing the mechanism of action of intervenolin, the research group has revealed that intervenolin has respiratory chain complex I inhibitory activity. Furthermore, they found that the inhibition of the oxidative phosphorylation pathway by the respiratory chain complex I inhibitor promoted the accumulation of lactate in the cells and the secretion of lactate outside the cells, and inhibited the growth of cancer cells by lowering the pH inside and outside the cells. This acidification-mediated anticancer mechanism of the respiratory chain complex I inhibitors is not related to energy depletion and is completely new as an anticancer mechanism of compounds. Moreover, since the degree of acidification is enhanced by stromal cells present in the tumor, it is expected to be applied to drug discovery research for pancreatic cancer, which is known to have abundant stromal cells.

Original article

iScience doi:10.1016/j.isci.2021.103497

J. Yoshida, T. Ohishi, H. Abe, S. Ohba, H. Inoue, I. Usami, M. Amemiya, R. Oriez, C. Sakashita, S. Dan, M. Sugawara, T. Kawaguchi, J. Ueno, Y. Asano, A. Ikeda, M. Takamatsu, G. Amori, Y. Kondoh, K. Honda, H. Osada, T. Noda, T. Watanabe, T. Shimizu, M. Shibasaki, M. Kawada,

"Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment".

Contact

Yasumitsu Kondoh; Senior Research Scientist

Hiroyuki Osada; Group Director

Chemical Biology Research Group