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. 5fluorouracil (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.

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.

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Vitamin K (VK) and vitamin D (VD) deficiency/insufficiency is a common feature of chronic kidney disease (CKD), leading to impaired bone quality and a higher risk of fractures. CKD patients, with disturbances in VK and VD metabolism, do not have sufficient levels of these vitamins for maintaining normal bone formation and mineralization. So far, there has been no consensus on what serum VK and VD levels can be considered sufficient in this particular population. Moreover, there are no clear guidelines how supplementation of these vitamins should be carried out in the course of CKD. Based on the existing results of preclinical studies and clinical evidence, this review intends to discuss the effect of VK and VD on bone remodeling in CKD. Although the mechanisms of action and the effects of these vitamins on bone are distinct, we try to find evidence for synergy between them in relation to bone metabolism, to answer the question of whether combined supplementation of VK and VD will be more beneficial for bone health in the CKD population than administering each of these vitamins separately.

An increase in the peripheral synthesis of serotonin and kynurenine, observed during the chronic kidney disease (CKD) course, is negatively associated with bone health. Serotonin and kynurenine are connected by the common precursor, tryptophan. LP533401 is an inhibitor of peripheral serotonin synthesis. This study aimed to establish if the inhibition of serotonin synthesis by LP533401 may affect the kynurenine pathway activity in bone tissue and its potential consequence with regard to osteogenesis and bone mineral status. Nephrectomized rats were treated with LP533401 at a dose of 30 and 100 mg/kg daily for eight weeks. Tryptophan and kynurenine concentrations were determined, and tryptophan 2,3-dioxygenase (TDO) expression was assessed. We discovered the presence of a TDO-dependent, paracrine kynurenic system in the bone of rats with CKD. Its modulation during LP533401 treatment was associated with impaired bone mineral status. Changes in TDO expression affecting the kynurenine pathway activity were related to the imbalance between peripheral serotonin and 25-hydroxyvitamin D. There were also close associations between the expression of genes participating in osteoblastogenesis and activation of the kynurenine pathway in the bones of LP53301-treated rats. Our results represent the next step in studying the role of tryptophan metabolites in renal osteodystrophy.