MM-129 as a Novel Inhibitor Targeting PI3K/AKT/mTOR and PD-L1 in Colorectal Cancer

Background and aims: The purpose of the present study was to examine the pharmacodynamics features of MM-129 (1,2,4-triazine derivative) as a novel promising drug candidate against colon cancer. Methods: MM-129 was assessed for antitumor activity through an in vivo study on Cby.Cg-Foxn1nu/cmdb mice....

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Bibliographic Details
Published in:Cancers 2021-06, Vol.13 (13), p.3203
Main Authors: Hermanowicz, Justyna Magdalena, Pawlak, Krystyna, Sieklucka, Beata, Czarnomysy, Robert, Kwiatkowska, Iwona, Kazberuk, Adam, Surazynski, Arkadiusz, Mojzych, Mariusz, Pawlak, Dariusz
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
5-Fluorouracil
AKT protein
Antitumor activity
Cancer therapies
Cell culture
Cell cycle
Cell division
Chemoresistance
Chemotherapy
Colon cancer
Colorectal cancer
Colorectal carcinoma
Cyclin-dependent kinase 2
Cyclin-dependent kinases
Experiments
G1 phase
Immunological tolerance
Intracellular
Kinases
Medical prognosis
Monoclonal antibodies
PD-L1 protein
Pharmacodynamics
Polyclonal antibodies
Prostate
Proteins
TOR protein
Triazine
Tumorigenesis
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Summary:Background and aims: The purpose of the present study was to examine the pharmacodynamics features of MM-129 (1,2,4-triazine derivative) as a novel promising drug candidate against colon cancer. Methods: MM-129 was assessed for antitumor activity through an in vivo study on Cby.Cg-Foxn1nu/cmdb mice. The mechanistic studies investigated cellular affinity of a new 1,2,4-triazine derivative by measuring levels of intracellular/extracellular signal molecules participating in tumorigenesis. Results: The results revealed that MM-129 significantly reduced tumor growth in mice challenged with DLD-1 and HT-29 cells. It exerted the ability to inhibit intracellular molecules promoting tumorigenesis and inducing cell cycle arrest, like Akt, mTOR, and CDK2. Simultaneously, it was able to downregulate PD-L1 expression, which involves immunological self-tolerance. Combined administration of MM-129 and 5-fluorouracil (5-FU) additionally amplified these effects, which were manifest as an increase population of cells in the G0/G1 phase. Conclusions: A novel 1,2,4-triazine derivative with a dual mechanism of antitumor activity—MM-129, may act as a chemosensitizer, overcoming chemoresistance against 5-FU, the first-line agent in the chemotherapy of colon cancer.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13133203