Oxidative tryptamine dimers from Corynebacterium durum directly target survivin to induce AIF-mediated apoptosis in cancer cells

• Published in: Biomedicine & pharmacotherapy Vol. 173; p. 116335
• Main Authors: Kim, Soyoung, Lee, Munseon, Kim, Nam-Yi, Kwon, Yun-Suk, Nam, Gi Suk, Lee, Kyounghoon, Kwon, Kang Mu, Kim, Dae Keun, Hwang, In Hyun
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.04.2024; Elsevier
• Subjects: Anticancer; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis Inducing Factor; Cell Line, Tumor; Cell Proliferation; Corynebacterium; Corynebacterium durum; Drug Screening Assays, Antitumor; Durumamide; Humans; Molecular Structure; Neoplasms - drug therapy; Oxidative Stress; Structure-Activity Relationship; Survivin; Tryptamine; Tryptamines - pharmacology; Tryptamines - therapeutic use; Tryptamine; HMBC; DARTS; PARP; SIR-2.1; Survivin; HMQC; Durumamide; IAPs; PI; Corynebacterium durum; Anticancer; AIF; Apoptosis
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2024.116335

Accumulating evidence indicates that microbial communities in the human body crucially affect health through the production of chemical messengers. However, the relationship between human microbiota and cancer has been underexplored. As a result of a biochemical investigation of the commensal oral microbe, Corynebacterium durum, we identified the non-enzymatic transformation of tryptamine into an anticancer compound, durumamide A (1). The structure of 1 was determined using LC-MS and NMR data analysis as bis(indolyl)glyoxylamide, which was confirmed using one-pot synthesis and X-ray crystallographic analysis, suggesting that 1 is an oxidative dimer of tryptamine. Compound 1 displayed cytotoxic activity against various cancer cell lines with IC50 values ranging from 25 to 35 μM. A drug affinity responsive target stability assay revealed that survivin is the direct target protein responsible for the anticancer effect of 1, which subsequently induces apoptosis-inducing factor (AIF)-mediated apoptosis. Inspired by the chemical structure and bioactivity of 1, a new derivative, durumamide B (2), was synthesized using another indole-based neurotransmitter, serotonin. The anticancer properties of 2 were similar to those of 1; however, it was less active. These findings reinforce the notion of human microbiota-host interplay by showing that 1 is naturally produced from the human microbial metabolite, tryptamine, which protects the host against cancer. [Display omitted]