New oligomycin derivatives inhibit anchorage-independent growth of pancreatic cancer cells

Daisuke Tatsuda; Masahide Amemiya; Chisato Nosaka; Yumiko Kubota; Ryuichi Sawa; Hideyuki Muramatsu; Masayuki Igarashi; Junjiro Yoshida; Tomokazu Ohishi; Manabu Kawada

doi:10.1038/s41429-025-00832-9

New oligomycin derivatives inhibit anchorage-independent growth of pancreatic cancer cells

J Antibiot (Tokyo). 2025 Jun 2. doi: 10.1038/s41429-025-00832-9. Online ahead of print.

Authors

Affiliations

¹ Laboratory of Oncology, Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan.
² Laboratory of Molecular Structure Analysis, Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan.
³ Laboratory of Microbiology, Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan.
⁴ Institute of Microbial Chemistry (BIKAKEN), Numazu branch, Numazu-shi, Shizuoka, Japan.
⁵ Laboratory of Oncology, Institute of Microbial Chemistry (BIKAKEN), Shinagawa-ku, Tokyo, Japan. kawadam@bikaken.or.jp.

^# Contributed equally.

PMID: 40456946
DOI: 10.1038/s41429-025-00832-9

Abstract

Cancer stem cells (CSCs) play a crucial role in cancer progression, recurrence, and therapy resistance through their abilities to self-renew, differentiate, and evade treatment. Disrupting the interaction between CSCs and their tumor microenvironment, especially cancer-associated fibroblasts (CAFs), represents a promising therapeutic strategy. We screened microbial metabolites to identify compounds that specifically inhibit anchorage-independent (3D) growth, a key characteristic of CSCs, in the presence of CAF-conditioned medium (CAF-CM). Two new oligomycin analogs, oligomycins EX-1 (1) and 2 (2), were successfully isolated from Nocardia sp. MK165-SF8. Structural analysis using NMR and MS techniques revealed their distinctive chemical characteristics, particularly the presence of an exomethylene group. In biological assays, 1 and 2 demonstrated potent inhibitory activity against mitochondrial complex V, comparable to oligomycin A. Additionally, they showed enhanced effectiveness in suppressing both 3D growth and the expression of CD44 variants in pancreatic cancer cells cultured in CAF-CM.