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Assessment of an Anticancer Effect of the Simultaneous Administration of MM-129 and Indoximod in the Colorectal
Iwona Kwiatkowska1, Justyna Magdalena Hermanowicz1,2, Robert Czarnomysy3
1Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland.
Abstract:
(1) Background: The purpose of the given study was to examine the antitumor activity of the simultaneous administration of MM-129, a 1,2,4-triazine derivative, and indoximod (IND), the kynurenine pathway inhibitor, toward colon cancer. (2) Methods: The efficiency of the co-administration of the studied compounds was assessed in xenografted zebrafish embryos. Then, the effects of the combined administration of compounds on cellular processes such as cell viability, apoptosis, and intracellular signaling pathways were evaluated. In vitro studies were performed using two colorectal cancer cell lines, namely, DLD-1 and HT-29. (3) Results: The results indicated that the simultaneous application of MM-129 and indoximod induced a stronger inhibition of tumor growth in zebrafish xenografts. The combination of these compounds intensified the process of apoptosis by lowering the mitochondrial potential, enhancing the externalization of phosphatidylserine (PS) and activation of caspases. Additionally, the expression of protein kinase B (AKT) and indoleamine 2,3-dioxygenase-(1IDO1) was disrupted under the applied compound combination. (4) Conclusions: Simultaneous targeting of ongoing cell signaling that promotes tumor progression, along with inhibition of the kynurenine pathway enzyme IDO1, results in the enhancement of the antitumor effect of the tested compounds against the colon cancer cells.
Insights
Combining MM-129, a triazine derivative, and indoximod (IND), a kynurenine pathway inhibitor, significantly enhances antitumor activity against colon cancer by promoting apoptosis and disrupting key signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Colon cancer remains a significant global health challenge.
- Targeting tumor progression and immune evasion pathways offers therapeutic potential.
- Indoleamine 2,3-dioxygenase (IDO1) is implicated in tumor immune evasion.
Purpose of the Study:
- To evaluate the combined antitumor efficacy of MM-129 and indoximod (IND) in colon cancer.
- To investigate the impact of this combination on cellular processes and signaling pathways.
- To assess the synergistic effects in preclinical colon cancer models.
Main Methods:
- In vivo studies using xenografted zebrafish embryos to assess tumor growth inhibition.
- In vitro evaluation of cell viability, apoptosis, and intracellular signaling in DLD-1 and HT-29 colon cancer cell lines.
- Analysis of mitochondrial potential, phosphatidylserine externalization, and caspase activation.
Main Results:
- Simultaneous administration of MM-129 and indoximod demonstrated superior tumor growth inhibition in zebrafish xenografts.
- The combination therapy significantly enhanced apoptosis induction, evidenced by decreased mitochondrial potential and increased PS externalization and caspase activation.
- Disruption of protein kinase B (AKT) and indoleamine 2,3-dioxygenase (IDO1) expression was observed.
Conclusions:
- Combined targeting of tumor progression signaling and IDO1 inhibition potentiates the antitumor effects against colon cancer.
- The synergistic action enhances apoptosis, suggesting a promising therapeutic strategy.
- This combination therapy warrants further investigation for colon cancer treatment.
