Cytostatic Bacterial Metabolites Interfere with 5-Fluorouracil, Doxorubicin and Paclitaxel Efficiency in 4T1 Breast Cancer Cells

• Published in: Molecules (Basel, Switzerland) Vol. 29; no. 13; p. 3073
• Main Authors: Schwarcz, Szandra, Nyerges, Petra, Bíró, Tímea Ingrid, Janka, Eszter, Bai, Péter, Mikó, Edit
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-07-2024
• Subjects: 5-fluorouracil; Acids; Animals; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacology; Bacteria - drug effects; Bacteria - metabolism; Biological activity; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Collaboration; Cyclin-dependent kinases; Cytostatic Agents - pharmacology; Development and progression; doxorubicin; Doxorubicin - pharmacology; Drug resistance; Efficiency; Female; Fluorouracil - pharmacology; gemcitabine; Humans; Indoles - pharmacology; irinotecan; Kinases; Metabolism; Metabolites; Metastasis; methotrexate; Mice; Oxidative stress; Paclitaxel - pharmacology; rucaparib; Stem cells; Hungary; United States > US; 5-fluorouracil; indolepropionic acid; paclitaxel; irinotecan; rucaparib; cell proliferation; indoxylsulfate; breast cancer; methotrexate; gemcitabine; doxorubicin; cadaverine
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29133073

The microbiome is capable of modulating the bioavailability of chemotherapy drugs, mainly due to metabolizing these agents. Multiple cytostatic bacterial metabolites were recently identified that have cytostatic effects on cancer cells. In this study, we addressed the question of whether a set of cytostatic bacterial metabolites (cadaverine, indolepropionic acid and indoxylsulfate) can interfere with the cytostatic effects of the chemotherapy agents used in the management of breast cancer (doxorubicin, gemcitabine, irinotecan, methotrexate, rucaparib, 5-fluorouracil and paclitaxel). The chemotherapy drugs were applied in a wide concentration range to which a bacterial metabolite was added in a concentration within its serum reference range, and the effects on cell proliferation were assessed. There was no interference between gemcitabine, irinotecan, methotrexate or rucaparib and the bacterial metabolites. Nevertheless, cadaverine and indolepropionic acid modulated the Hill coefficient of the inhibitory curve of doxorubicin and 5-fluorouracil. Changes to the Hill coefficient implicate alterations to the kinetics of the binding of the chemotherapy agents to their targets. These effects have an unpredictable significance from the clinical or pharmacological perspective. Importantly, indolepropionic acid decreased the IC
value of paclitaxel, which is a potentially advantageous combination.