In vivo study of the antitumor activity of indole-3-propionic acid and its combination with chemotherapy drugs

Background. Colorectal cancer (CRC) is characterized by high mortality and the development of therapy resistance. Indole-3-propionic acid (IPA), a gut microbiota-derived metabolite, shows promise in treating colorectal cancer (CRC) by strengthening antitumor immunity and improving chemotherapy effcacy.
The aim of the study was to evaluate the antitumor activity of indole-3-propionate in vivo using a mouse model of colorectal cancer.
Material and Methods. The experiment was conducted on 42 female mice with subcutaneous CT26 CRC. After reaching a tumor volume of 50–60 мм³ , the animals were randomized into 6 groups (n=7): control (0.9 % NaCl saline i.p. and p.o.), IPA monotherapy (6 mg/kg, p.o.), 5-fuorouracil (5-FU) (25 mg/kg, i.p.), oxaliplatin (OXA) (10 mg/kg, i.p.), combination IPA (6 mg/kg, p.o.) + 5-FU (25 mg/kg, i.p.) and IPA (6 mg/kg, p.o.) + OXA (10 mg/kg, i.p.). Drugs were administered 3 times per week (Mon, Wed, Fri) for 3 weeks. The results were assessed one week after the end of treatment. Tumor volume and tumor growth inhibition (TGI) percentage were evaluated. Statistical analysis was performed using the Mann-Whitney U-test.
Results. IPA monotherapy had no signifcant effect (TGI=5.0 %). Chemotherapeutic agents in monotherapy demonstrated moderate activity: TGI 22.9 % for 5-FU and 19.4 % for OXA. The greatest effcacy was achieved in the combination therapy groups: TGI 31.9 % for IPA + 5-FU and 30.1 % for IPA + OXA. Statistically signifcant growth inhibition in these groups was registered from day 18 (4 days earlier than with cytostatic monotherapy). Toxicity, assessed by body weight dynamics, was absent in all groups.
Discussion. The results obtained demonstrate that IPA does not possess independent cytotoxic activity against CT26 tumor cells. However, its potential in combination with standard chemotherapeutic drugs was revealed. Earlier and more pronounced TGI in the combination therapy groups indicates the ability of IPA to accelerate the development of a therapeutic response.
Conclusion. IPA potentiates the antitumor activity of 5-FU and OXA on the CT26 CRC model without increasing systemic toxicity. The obtained data justify further study of the mechanisms of IPA synergy with chemotherapeutic agents and its effcacy in other malignant neoplasms.

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