Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer
Justyna Magdalena Hermanowicz, Anna Szymanowska, Beata Sieklucka, Robert Czarnomysy, Krystyna Pawlak, Anna Bielawska, Krzysztof Bielawski, Joanna Kałafut, Alicja Przybyszewska-Podstawka, Arkadiusz Surażyński, Adolfo Rivero‐Müller, Mariusz Mojzych, Dariusz Pawlak
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in men and in women. The impact of the new pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide (MM-129) was evaluated against human colon cancer in vitro and in zebrafish xenografts. Our results show that this new synthesised compound effectively inhibits cell survival in BTK-dependent mechanism. Its effectiveness is much higher at a relatively low concentration as compared with the standard chemotherapy used for CRC, i.e. 5-fluorouracil (5-FU). Flow cytometry analysis after annexin V-FITC and propidium iodide staining revealed that apoptosis was the main response of CRC cells to MM-129 treatment. We also found that MM-129 effectively inhibits tumour development in zebrafish embryo xenograft model, where it showed a markedly synergistic anticancer effect when used in combination with 5-FU. The above results suggest that this novel heterofused 1,2,4-triazine derivative may be a promising candidate for further evaluation as chemotherapeutic agent against CRC.