Modulating the microbiome as an approach to anticancer drug development
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 <i><i>Lactobacillus</i></i> 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.
Authors
- Chengnan Wu (ORCID: https://orcid.org/0000-0002-0740-7546)
- Kwan T. Chow (ORCID: https://orcid.org/0000-0003-1012-0797)
- Anton P. Tyurin (ORCID: https://orcid.org/0000-0002-5597-6161)
- Eunice Dotse (ORCID: https://orcid.org/0000-0002-1118-6942)
- Elena E. Bardina
- Anna A. Kirsanova (ORCID: https://orcid.org/0000-0003-2728-3525)
- Maria V. Babak (ORCID: https://orcid.org/0000-0002-2009-7837)
- William Chi Shing Cho (ORCID: https://orcid.org/0000-0003-4174-4586)
- Nikolay Karnaukhov (ORCID: https://orcid.org/0000-0003-0889-2720)
- Даниил А. Русанов (ORCID: https://orcid.org/0000-0002-7573-3730)
- Alexey V. Tkachev⊥ (ORCID: https://orcid.org/0000-0002-6310-0936)
- Artem L. Gushchin (ORCID: https://orcid.org/0000-0003-3214-1433)
- Ho Sung Choe (ORCID: https://orcid.org/0000-0002-1973-3568)
- Владимир Кушнарев (ORCID: https://orcid.org/0000-0003-4608-9349)
- Jemma Arakelyan (ORCID: https://orcid.org/0000-0002-0012-8536)
- Vladislav Yu. Komarov (ORCID: https://orcid.org/0000-0001-7519-1719)
- Nikita Y. Shmelev (ORCID: https://orcid.org/0000-0003-4845-2674)
- Yuliya V. Zakalyukina (ORCID: https://orcid.org/0000-0001-8943-5761)
- Eugene S. Vasilyev (ORCID: https://orcid.org/0000-0001-7476-3826)
- Gerald D’Cruz
Institutions
- Russian Academy of Sciences (RU)
- City University of Hong Kong (HK)
- Lomonosov Moscow State University (RU)
- Discovery Centre (CA)
- Moscow Clinical Scientific Center (RU)
- Novosibirsk Institute of Organic Chemistry (RU)
- Institute of Bioorganic Chemistry (RU)
- Queen Elizabeth Hospital (GB)
- Drug Discovery Laboratory (Norway) (NO)
- Institute of Bioorganic Chemistry (BY)
- Nikolaev Institute of Inorganic Chemistry (RU)
- Moscow State University (TJ)
- University of Hong Kong (HK)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-10-28
- DOI
- https://doi.org/10.1073/pnas.2417269122
- Citations
- 1
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 0.81