Modulating the microbiome as an approach to anticancer drug development
Abstract
Recent studies have suggested that the commensal microbiome positively affects cancer prognosis and treatment outcomes. However, only a few strategies for regulating the microbiome composition have been reported. In this study, we identified gold(I) complexes that selectively inhibited nonbeneficial bacterial strains in vitro without affecting commensal Lactobacillus strains. In contrast, clinically used drugs demonstrated comparable effects on both commensal and noncommensal strains. Consistent with the in vitro results, the selected gold(I) complex induced favorable changes in the intratumoral and gastrointestinal microbiomes in vivo. Furthermore, its anticancer efficacy was found to be dependent on the composition of microbiome and correlated with the production of short-chain fatty acid bacterial metabolites. Structure–activity relationship studies have dissected the contribution of each structural component in both the in vivo efficacy and microbiome-modulating properties. Transcriptomic analysis of tumors revealed microbiome-associated gene signaling pathways. These findings provide valuable insights for future research on microbiome-modulating anticancer drugs, presenting potential avenues to optimize cancer treatment outcomes and mitigate side effects such as gastrointestinal dysbiosis. Furthermore, our study provides insights into the involvement of microbiome in the mechanism of action of metal-based chemotherapeutics.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Jemma Arakelyan
Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong, SAR 999077, People’s Republic of China
Ho-Jung Choe
Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR 999077, People’s Republic of China
Chengnan Wu
Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR 999077, People’s Republic of China
Daniil A. Rusanov
Department of Chemistry, Drug Discovery Lab, City University of Hong Kong
Elena E. Bardina
A.V. Nikolaev Institute of Inorganic Chemistry, Siberian Branch of Russian Academy of Sciences
Anna A. Kirsanova
Department of Chemistry, Drug Discovery Lab, City University of Hong Kong
Yuliya V. Zakalyukina
Department of Soil Science, Lomonosov Moscow State University
Nikita Y. Shmelev
A.V. Nikolaev Institute of Inorganic Chemistry, Siberian Branch of Russian Academy of Sciences
Anton P. Tyurin
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry
Vladislav Y. Komarov
A.V. Nikolaev Institute of Inorganic Chemistry, Siberian Branch of Russian Academy of Sciences
Vladimir Kushnarev
Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong SAR 999077, People’s Republic of China
Nikolay S. Karnaukhov
Moscow Clinical Research Center named after A.S. Loginov
Gerald D’Cruz
Department of Chemistry, Drug Discovery Lab, City University of Hong Kong
Eugene S. Vasilyev
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences
Eunice Dotse
Department of Biomedical Sciences, City University of Hong Kong
Kwan T. Chow
Department of Biomedical Sciences, City University of Hong Kong
William C. Cho
Department of Clinical Oncology, Queen Elizabeth Hospital
Alexey V. Tkachev
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian Academy of Sciences
Artem L. Gushchin
A.V. Nikolaev Institute of Inorganic Chemistry, Siberian Branch of Russian Academy of Sciences
Maria V. Babak
Drug Discovery Lab, Department of Chemistry, City University of Hong Kong, 83 Tat Chee Avenue, Hong Kong, SAR 999077, People’s Republic of China