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Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.

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Background/Aim: The occurrence of BRAF V600E mutation causes an up-regulation of the B-raf kinase activity leading to the stabilization of hypoxia-inducible factor 1-alpha (HIF-1α) -the promoter of the 6-phosphofructo-2kinase/fructose-2,6-biphosphatase 3 (PFKFB3) enzyme. The aim of the study was to examine the effect of the (2E)-3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), as an inhibitor of PFKFB3, on human melanoma cells (A375) with endogenous BRAF V600E mutation. Materials and Methods: A375 cells were exposed to different concentrations of 3PO and the following tests were performed: docking, cytotoxicity assay, immunocytochemistry staining glucose uptake, clonogenic assay, holotomography imaging, and flow cytometry. Results: Our studies revealed that 3PO presents a dose-dependent and time-independent cytotoxic effect and promotes apoptosis of A375 cells. Furthermore, the obtained data indicate that 3PO induces cell cycle arrest in G1/0 and glucose uptake reduction. Conclusion: Taking all together, our research demonstrated a here should be proapoptotic and antiproliferative effect of 3PO on A375 human melanoma cells.Malignant melanoma is a neoplasm derived from melanocytes (pigment-containing cells) localized typically in the skin as well as in the eye, intestines, inner ear and meninges (1). Its cutaneous form is considered as the most aggressive and the deadliest type of skin cancer. The primary locus of tumor exhibits a predilection for early metastasis, which can occur even from thin carcinomas. Therefore, the early diagnosis of melanoma is essential for the further success of the applied treatment (1).Depending on the tumor's features, possible therapeutic methods may include surgery, chemotherapy, radiotherapy, immunotherapy or molecularly targeted therapies (2). Surgical excision of melanoma at the earliest possible stage is essential for a successful therapeutic outcome. Radiotherapy may be recommended for the treatment of skin, bone and brain metastases (3). Chemotherapy with dacarbazine, and temozolomide was the first systemic treatment applied in advanced melanoma; however, overall survival rates (OS) did not show significant improvement (4). In a phase III study comparing dacarbazine and temozolomide the response rate was 12% and 13%, respectively (5). None of these two alkylating agents affect a specific molecular pathway, thus they cannot be used in personalized oncology. Despite novel reports on new therapy achievements in the field of immunotherapy or biological treatment, these methods are insufficient and burdened with certain disadvantages and side-effects (6). This causes an urgent need for finding new treatment options for melanoma.BRAF (v-raf murine sarcoma viral oncogene homolog B) gene is located at chromosome 7 (7q34) and encodes B-raf 2613

Cancers are one of the leading causes of deaths affecting millions of people around the world, therefore they are currently a major public health problem. The treatment of cancer is based on surgical resection, radiotherapy, chemotherapy or immunotherapy, much of which is often insufficient and cause serious, burdensome and undesirable side effects. For many years, assorted secondary metabolites derived from plants have been used as antitumor agents. Recently, researchers have discovered a large number of new natural substances which can effectively interfere with cancer cells’ metabolism. The most famous groups of these compounds are topoisomerase and mitotic inhibitors. The aim of the latest research is to characterize natural compounds found in many common foods, especially by means of their abilities to regulate cell cycle, growth and differentiation, as well as epigenetic modulation. In this paper, we focus on a review of recent discoveries regarding nature-derived anticancer agents.