Justyna Magdalena Hermanowicz1,2, Krystyna Pawlak3, Beata Sieklucka1, Robert Czarnomysy4, Iwona Kwiatkowska1, Adam Kazberuk5, Arkadiusz Surazynski5, Mariusz Mojzych6, Dariusz Pawlak1. 1. Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland. 2. Department of Clinical Pharmacy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland. 3. Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland. 4. Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland. 5. Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland. 6. Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland.
Abstract
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.
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.