Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, β-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT.

Acetylation and deacetylation are posttranslational modifications (PTMs) which affect the regulation of chromatin structure and its remodeling. Acetylation of histone 3 at lysine placed on position 18 (H3K18Ac) plays an important role in driving progression of many types of cancer, including breast, colon, lung, hepatocellular, pancreatic, prostate, and thyroid cancer. The aim of this review is to analyze and discuss the newest findings regarding the role of H3K18Ac and acetylation of other histones in carcinogenesis. We summarize the level of H3K18Ac in different cancer cell lines and analyze its association with patients’ outcomes, including overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS). Finally, we describe future perspectives of cancer therapeutic strategies based on H3K18 modifications.

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.

Follicle stimulating hormone (FSH) plays a key role in human reproduction through, among others, induction of spermatogenesis in men and production of estrogen in women. The function FSH is performed upon binding to its cognate receptor—follicle-stimulating hormone receptor (FSHR) expressed on the surface of target cells (granulosa and Sertoli cells). FSHR belongs to the family of G protein-coupled receptors (GPCRs), a family of receptors distinguished by the presence of various signaling pathway activation as well as formation of cross-talking aggregates. Until recently, it was claimed that the FSHR occurred naturally as a monomer, however, the crystal structure as well as experimental evidence have shown that FSHR both self-associates and forms heterodimers with the luteinizing hormone/chorionic gonadotropin receptor—LHCGR. The tremendous gain of knowledge is also visible on the subject of receptor activation. It was once thought that activation occurs only as a result of ligand binding to a particular receptor, however there is mounting evidence of trans-activation as well as biased signaling between GPCRs. Herein, we describe the mechanisms of aforementioned phenomena as well as briefly describe important experiments that contributed to their better understanding.

Recombinant human erythropoietin (Epo) is an effective and convenient treatment for cancer-related anaemia. In our study for the first time, we evaluated the effect of simultaneous use of Epo and Bruton's tyrosine kinase (BTK) inhibitor LFM-A13 on the viability and tumour development of breast cancer cells. The results demonstrated that Epo significantly intensifies the anticancer activity of LFM-A13 in MCF-7 and MDA-MB-231. The featured therapeutic scheme efficiently blocked the tumour development in zebrafish experimental cancer model. Epo and LFM-A13 administered together resulted in effective cell killing, accompanied by attenuation of the BTK signalling pathways, loss of mitochondrial membrane potential (MMP), accumulation of apoptotic breast cancer cells with externalised PS, a slight increase in phase G0/G1 and a reduction in cyclin D1 expression. Simultaneous use of Epo with LFM-A13 inhibited early stages of tumour progression. This therapeutic scheme may be rationale for further possible research.

Experimental Approach: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in men and in women. It's expected to cause about 53,200 deaths during 2020. An effective drug for therapy and prognosis after surgery still does not exist. Therefore, the search for new lead structures and chemical entities for the development of new effective anticancer agents is an increasingly important task in medicinal chemistry. This trend of global research includes work on the use of 1,2,4-triazine scaffold as a source for the design of biologically relevant molecules with well-known broad biological applications. A series of new pyrazolo[4,3-e]tetrazolo [4,5-b][1,2,4]triazine sulfonamides were designed, synthesized, and assessed as anticancer activity agents. Experimental Approach: The impact of two selected compounds, MM-128, and MM-129 (MMs), were evaluated against human colon cancer in in vitro and in zebrafish embryo xenograft model. Key Results: Our results show that the new synthesized compounds effectively inhibit cell survival and DNA synthesis in both DLD-1 and HT-29 cell lines. Their effectiveness is much higher as compared with the standard chemotherapy used for colorectal cancer, i.e. 5-fluorouracil. Flow cytometry analysis after annexin V-FITC and propidium iodide staining revealed that apoptosis was the main response of colorectal cancer cells to MMs treatment. We also found that MM-129 effectively inhibits tumor development in both DLD-1 and HT-29 zebrafish xenografts. Conclusion and Implications: New pyrazolo[4,3-e]tetrazolo [4,5-b][1,2,4]triazine sulfonamides may be new candidates for further evaluation as chemotherapeutic agents against colorectal cancer.Abbreviations 5-FU: 5-fluorouracil AlF : apoptosis inducing factorApaf-1: apoptotic protease activating factor 1 Bak:Bcl-2 -homologous antagonist/killer Bax: Bcl-2-associated X protein Bcl-2: antiapoptotic protein Bcr-Abl: tyrosine kinase Bid: Bax-like BH3 protein tBid: truncated BIDDLD-1: cell line of human colorectal adenocarcinomaFADD: Fas-associated death domain protein HT-29: cell line of human colorectal adenocarcinoma hpf: hours post-fertilization hpt: hour post-treatment MMP:mitochondrial membrane potential MMs: MM-128, MM-129PCD : programmed cell death PS: phosphatidyloserineROS : roscovitine