Balancing Histone Deacetylase (HDAC) Inhibition and Drug-likeness: Biological and Physicochemical Evaluation of Class I Selective HDAC Inhibitors

Herein we report the structure-activity and structure-physicochemical property relationships of a series of class I selective ortho-aminoanilides targeting the “foot-pocket” in HDAC1&2. To balance the structural benefits and the physicochemical disadvantages of these substances, we started with a set of HDACi related to tacedinaline (CI-994) and evaluated their solubility, lipophilicity (log D_7.4) and inhibition of selected HDAC isoforms. Subsequently, we selected the most promising “capless” HDACi and transferred its ZBG to our previously published scaffold featuring a peptoid-based cap group. The resulting hit compound 10 c ( LSH-A54) showed favorable physicochemical properties and is a potent, selective HDAC1/2 inhibitor. The following evaluation of its slow binding properties revealed that LSH-A54 binds tightly to HDAC1 in an induced-fit mechanism. The potent HDAC1/2 inhibitory properties were reflected by attenuated cell migration in a modified wound healing assay and reduced cell viability in a clonogenic survival assay in selected breast cancer cell lines.     

Targeting Epigenetic Regulators for Endometrial Cancer Therapy: Its Molecular Biology and Potential Clinical Applications

Endometrial cancer is one of the most frequently diagnosed gynecological malignancies worldwide. However, its prognosis in advanced stages is poor, and there are only few available treatment options when it recurs. Epigenetic changes in gene function, such as DNA methylation, histone modification, and non-coding RNA, have been studied for the last two decades. Epigenetic dysregulation is often reported in the development and progression of various cancers. Recently, epigenetic changes in endometrial cancer have also been discussed. In this review, we give the main points of the role of DNA methylation and histone modification in endometrial cancer, the diagnostic tools to determine these modifications, and inhibitors targeting epigenetic regulators that are currently in preclinical studies and clinical trials.     

Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells

We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast cancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemically synthesized hybrid (N-hydroxy-N''-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation, and mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect. Cell cycle analysis showed a perturbation of the rate of progression through the cycle, with aspects of redistribution of cells over different cycle phases for the two treatments. In addition, the results suggest that the two distinct classes of compounds under investigation could induce cell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosis promotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. the combination approach in finely tuning the biological activities of target cells and also showing the hybrid compound as an additional promising drug-like molecule for the prevention or therapy of “aggressive” breast carcinoma.     

Multitarget Inhibition of Histone Deacetylase (HDAC) and Phosphatidylinositol-3-kinase (PI3K): Current and Future Prospects

The discovery of histone deacetylase (HDAC) inhibitors is a hot topic in the medicinal chemistry community regarding cancer research. This is related primarily to two factors: success in the clinic, e. g., the four FDA-approved HDAC inhibitors, and strong versatility to combine their pharmacophoric features to design new hybrid compounds with multitarget profiles. Thus, the selection of adequate pharmacophores to combine, i. e., combining targets that can result in a synergistic effect, is desirable, as it increases the probability of discovering a new useful therapeutic strategy. In this work, we highlight the design of multitarget HDAC/PI3K inhibitors. Although this approach is still in its early stages, many significant works have described the design and pharmacological evaluation of this new promising class of multitarget inhibitors, where compound CUDC-907, which is already in clinical trials, stands out. Therefore, the question emerges of whether there still space for the design and evaluation of new multitarget HDAC/PI3K inhibitors. When considering the selectivity profile of the described multitarget compounds, the answer appears to be in the affirmative, especially since the first examples of compounds with a certain selectivity profile only recently appeared in 2020.     

Synergistic Effect of Simultaneous versus Sequential Combined Treatment of Histone Deacetylase Inhibitor Valproic Acid with Etoposide on Melanoma Cells

Melanoma is the most lethal form of skin cancer, which is intrinsically resistant to conventional chemotherapy. Combination therapy has been developed to overcome this challenge and show synergistic anticancer effects on melanoma. Notably, the histone deacetylase inhibitor, valproic acid (VPA), has been indicated as a potential sensitizer of chemotherapy drugs on various metastatic cancers, including advanced melanoma. In this study, we explored whether VPA could serve as an effective sensitizer of chemotherapy drug etoposide (ETO) on B16-F10 and SK-MEL-2-Luc melanoma cell lines in response to drug-induced DNA damages. Our results demonstrated that the VPA-ETO simultaneous combined treatment and ETO pretreated sequential combined treatment generated higher inhibitory effectivities than the individual treatment of each drug. We found the VPA-ETO simultaneous combined treatment contributed to the synergistic inhibitory effect by the augmented DNA double-strand breaks, accompanied by a compromised homologous recombination activity. In comparison, the ETO pretreated sequential combined treatment led to synergistic inhibitory effect via enhanced apoptosis. Surprisingly, the enhanced homologous recombination activity and G2/M phase arrest resulted in the antagonistic effect in both cells under VPA pretreated sequential combined treatment. In summary, our findings suggested that sequential order and effective dose of drug administration in VPA-ETO combination therapy could induce different cellular responses in melanoma cells. Such understanding might help potentiate the effectiveness of melanoma treatment and highlight the importance of sequential order and effective dose in combination therapy.     

Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together

Histone deacetylase inhibitors (HDIs) are promising anti-cancer agents that inhibit proliferation of many types of cancer cells including breast carcinoma (BC) cells. In the present study, we investigated the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two HDIs, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), in luminal-like BC cells. The type of drug–drug interaction between CDDP and HDIs was determined by isobolographic analysis. MCF7 cells were genetically modified to express differential levels of Notch1 activity. The cytotoxic effect of SAHA or VPA was higher on cells with decreased Notch1 activity and lower for cells with increased Notch1 activity than native BC cells. The isobolographic analysis demonstrated that combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive or additive with tendency toward synergism interactions. Therefore, treatment of CDDP with HDIs could be used to optimize a combined therapy based on CDDP against Notch1-altered luminal BC. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of luminal-type BC with altered Notch1 activity.     

Rho-Kinase as a Target for Cancer Therapy and Its Immunotherapeutic Potential

Cancer immunotherapy is fast rising as a prominent new pillar of cancer treatment, harnessing the immune system to fight against numerous types of cancer. Rho-kinase (ROCK) pathway is involved in diverse cellular activities, and is therefore the target of interest in various diseases at the cellular level including cancer. Indeed, ROCK is well-known for its involvement in the tumor cell and tumor microenvironment, especially in its ability to enhance tumor cell progression, migration, metastasis, and extracellular matrix remodeling. Importantly, ROCK is also considered to be a novel and effective modulator of immune cells, although further studies are needed. In this review article, we describe the various activities of ROCK and its potential to be utilized in cancer treatment, particularly in cancer immunotherapy, by shining a light on its activities in the immune system.     

Teneurins: Role in Cancer and Potential Role as Diagnostic Biomarkers and Targets for Therapy

Teneurins have been identified in vertebrates as four different genes (TENM1-4), coding for membrane proteins that are mainly involved in embryonic and neuronal development. Genetic studies have correlated them with various diseases, including developmental problems, neurological disorders and congenital general anosmia. There is some evidence to suggest their possible involvement in cancer initiation and progression, and drug resistance. Indeed, mutations, chromosomal alterations and the deregulation of teneurins expression have been associated with several tumor types and patient survival. However, the role of teneurins in cancer-related regulatory networks is not fully understood, as both a tumor-suppressor role and pro-tumoral functions have been proposed, depending on tumor histotype. Here, we summarize and discuss the literature data on teneurins expression and their potential role in different tumor types, while highlighting the possibility of using teneurins as novel molecular diagnostic and prognostic biomarkers and as targets for cancer treatments, such as immunotherapy, in some tumors.     

The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application

Liver fibrosis results from repeated and persistent liver damage. It can start with hepatocyte injury and advance to inflammation, which recruits and activates additional liver immune cells, leading to the activation of the hepatic stellate cells (HSCs). It is the primary source of myofibroblasts (MFs), which result in collagen synthesis and extracellular matrix protein accumulation. Although there is no FDA and EMA-approved anti-fibrotic drug, antiviral therapy has made remarkable progress in preventing or even reversing the progression of liver fibrosis, but such a strategy remains elusive for patients with viral, alcoholic or nonalcoholic steatosis, genetic or autoimmune liver disease. Due to the complexity of the etiology, combination treatments affecting two or more targets are likely to be required. Here, we review the pathogenic mechanisms of liver fibrosis and signaling pathways involved, as well as various molecular targets for liver fibrosis treatment. The development of efficient drug delivery systems that target different cells in liver fibrosis therapy is also summarized. We highlight promising anti-fibrotic events in clinical trial and preclinical testing, which include small molecules and natural compounds. Last, we discuss the challenges and opportunities in developing anti-fibrotic therapies.     

Lunasin Sensitivity in Non-Small Cell Lung Cancer Cells Is Linked to Suppression of Integrin Signaling and Changes in Histone Acetylation

Lunasin is a plant derived bioactive peptide with both cancer chemopreventive and therapeutic activity. We recently showed lunasin inhibits non-small cell lung cancer (NSCLC) cell proliferation in a cell-line-specific manner. We now compared the effects of lunasin treatment of lunasin-sensitive (H661) and lunasin-insensitive (H1299) NSCLC cells with respect to lunasin uptake, histone acetylation and integrin signaling. Both cell lines exhibited changes in histone acetylation, with H661 cells showing a unique increase in H4K16 acetylation. Proximity ligation assays demonstrated lunasin interacted with integrins containing αv, α5, β1 and β3 subunits to a larger extent in the H661 compared to H1299 cells. Moreover, lunasin specifically disrupted the interaction of β1 and β3 subunits with the downstream signaling components phosphorylated Focal Adhesion Kinase (pFAK), Kindlin and Intergrin Linked Kinase in H661 cells. Immunoblot analyses demonstrated lunasin treatment of H661 resulted in reduced levels of pFAK, phosphorylated Akt and phosphorylated ERK1/2 whereas no changes were observed in H1299 cells. Silencing of αv expression in H661 cells confirmed signaling through integrins containing αv is essential for proliferation. Moreover, lunasin was unable to further inhibit proliferation in αv-silenced H661 cells. This indicates antagonism of integrin signaling via αv-containing integrins is an important component of lunasin’s mechanism of action.     

JIB-04, a Pan-Inhibitor of Histone Demethylases,Targets Histone-Lysine-Demethylase-Dependent AKT Pathway,Leading to Cell Cycle Arrest and Inhibition of Cancer Stem-Like Cell Properties in Hepatocellular Carcinoma Cells

JIB-04, a pan-histone lysine demethylase (KDM) inhibitor, targets drug-resistant cells, along with colorectal cancer stem cells (CSCs), which are crucial for cancer recurrence and metastasis. Despite the advances in CSC biology, the effect of JIB-04 on liver CSCs (LCSCs) and the malignancy of hepatocellular carcinoma (HCC) has not been elucidated yet. Here, we showed that JIB-04 targeted KDMs, leading to the growth inhibition and cell cycle arrest of HCC, and abolished the viability of LCSCs. JIB-04 significantly attenuated CSC tumorsphere formation, growth, relapse, migration, and invasion in vitro. Among KDMs, the deficiency of KDM4B, KDM4D, and KDM6B reduced the viability of the tumorspheres, suggesting their roles in the function of LCSCs. RNA sequencing revealed that JIB-04 affected various cancer-related pathways, especially the PI3K/AKT pathway, which is crucial for HCC malignancy and the maintenance of LCSCs. Our results revealed KDM6B-dependent AKT2 expression and the downregulation of E2F-regulated genes via JIB-04-induced inhibition of the AKT2/FOXO3a/p21/RB axis. A ChIP assay demonstrated JIB-04-induced reduction in H3K27me3 at the AKT2 promoter and the enrichment of KDM6B within this promoter. Overall, our results strongly suggest that the inhibitory effect of JIB-04 on HCC malignancy and the maintenance of LCSCs is mediated via targeting the KDM6B-AKT2 pathway, indicating the therapeutic potential of JIB-04.     

Potential Role of the Circadian Clock in the Regulation of Cancer Stem Cells and Cancer Therapy

Circadian rhythms, including sleep/wake cycles as well as hormonal, immune, metabolic, and cell proliferation rhythms, are fundamental biological processes driven by a cellular time-keeping system called the circadian clock. Disruptions in these rhythms due to genetic alterations or irregular lifestyles cause fundamental changes in physiology, from metabolism to cellular proliferation and differentiation, resulting in pathological consequences including cancer. Cancer cells are not uniform and static but exist as different subtypes with phenotypic and functional differences in the tumor microenvironment. At the top of the heterogeneous tumor cell hierarchy, cancer stem cells (CSCs), a self-renewing and multi-potent cancer cell type, are most responsible for tumor recurrence and metastasis, chemoresistance, and mortality. Phenotypically, CSCs are associated with the epithelial–mesenchymal transition (EMT), which confers cancer cells with increased motility and invasion ability that is characteristic of malignant and drug-resistant stem cells. Recently, emerging studies of different cancer types, such as glioblastoma, leukemia, prostate cancer, and breast cancer, suggest that the circadian clock plays an important role in the maintenance of CSC/EMT characteristics. In this review, we describe recent discoveries regarding how tumor intrinsic and extrinsic circadian clock-regulating factors affect CSC evolution, highlighting the possibility of developing novel chronotherapeutic strategies that could be used against CSCs to fight cancer.     

The Effect of Germination on Phenolic Compounds and Antioxidant Activity of Pulses

In this study the changes of phenolic compounds and antioxidant activity of four different pulses namely white bean (Phaseolus vulgaris L), Common vetch (Vicia sativa), Lentil (Lens culinaris) and Chickpea (Cicer arietinum) seeds before and after germination were investigated. Seeds germinated in dark chambers maintained near 100 % relative humidity at 20 °C. Three different solvents namely acetone, hexane and methanol were employed to extract the phenolic compounds present in the seeds and sprouts. Total content of phenolic compounds was measured by the Folin–Ciocalteu method and antioxidant activity determined by the delay in fat oxidation. Different concentrations of extracts (0.02 and 0.1 % w/w) were added to tallow and the stabilities of the treatments were determined by the peroxide value and induction period measurements to evaluate the antioxidant activities. The results indicated that the increases in phenolic content from dormant seed to sprouted seed were significant (P ≤ 0.05) in all the samples. The significant differences between induction periods of tallow treated with sprouted seed extracts were observed (P < 0.05). The results indicated that the greatest increase in stability was obtained when tallow was treated with a 0.1 % concentration of acetone chickpea sprout extract. The pulses' sprout flour or extract might be recommended for use as a source of natural antioxidants in functional foods.     

A Bimetallic Nanozyme with Cascade Effect for Synergistic Therapy of Cancer

Novel nanocomposites were constructed through encapsulation of Au nanoparticles and Ru nanoparticles into dendritic mesoporous silica (DMSN-Au-Ru NPs). These exhibit improved effects due to a cascade catalytic ability for the synergistic therapy of cancer. Au nanoparticles with glucose oxidase-like properties were found to catalyze the oxidation of glucose to produce H₂O₂, while Ru nanoparticles could decompose H₂O₂ and produce toxic ¹O₂ for improved photodynamic therapy (PDT). In addition, the nanocomposites were found to have good photothermal performance under irradiation by near-infrared (NIR) light. Both in vitro and in vivo experiments show that the nanocomposites have good therapeutic effects due to the cascade catalytic effect and synergistic effect. These findings provide an effective way to design a new generation of nanodrugs for highly efficient cancer treatment.     

Current Uses of Mushrooms in Cancer Treatment and Their Anticancer Mechanisms

Cancer is the leading cause of mortality worldwide. Various chemotherapeutic drugs have been extensively used for cancer treatment. However, current anticancer drugs cause severe side effects and induce resistance. Therefore, the development of novel and effective anticancer agents with minimal or no side effects is important. Notably, natural compounds have been highlighted as anticancer drugs. Among them, many researchers have focused on mushrooms that have biological activities, including antitumor activity. The aim of this review is to discuss the anticancer potential of different mushrooms and the underlying molecular mechanisms. We provide information regarding the current clinical status and possible modes of molecular actions of various mushrooms and mushroom-derived compounds. This review will help researchers and clinicians in designing evidence-based preclinical and clinical studies to test the anticancer potential of mushrooms and their active compounds in different types of cancers.     

The Potential Role of Lycopene for the Prevention and Therapy of Prostate Cancer: From Molecular Mechanisms to Clinical Evidence

Lycopene is a phytochemical that belongs to a group of pigments known as carotenoids. It is red, lipophilic and naturally occurring in many fruits and vegetables, with tomatoes and tomato-based products containing the highest concentrations of bioavailable lycopene. Several epidemiological studies have linked increased lycopene consumption with decreased prostate cancer risk. These findings are supported by in vitro and in vivo experiments showing that lycopene not only enhances the antioxidant response of prostate cells, but that it is even able to inhibit proliferation, induce apoptosis and decrease the metastatic capacity of prostate cancer cells. However, there is still no clearly proven clinical evidence supporting the use of lycopene in the prevention or treatment of prostate cancer, due to the only limited number of published randomized clinical trials and the varying quality of existing studies. The scope of this article is to discuss the potential impact of lycopene on prostate cancer by giving an overview about its molecular mechanisms and clinical effects.     

改性三乙醇胺化合物的合成及其对水泥助磨性能的影响

本文合成了五种改性三乙醇胺化合物,即三乙醇胺硫酸酯(GA_1)、三乙醇胺乙酸酯(GA_2)、三乙醇胺马来酸酯(GA_3)、马来酸三乙醇胺盐(GA_4)和油酸三乙醇胺盐(GA_5).以三乙醇胺为参比项,在不同添加量下,各化合物与水泥熟料和石膏在闭路磨机内粉磨一定的时间,通过分析粉体的比表面积(SSA)、粒径分布、中值粒径(D_(50)) 、均匀性系数(n)和强度,探讨了改性后的三乙醇胺会对水泥助磨效果产生的影响,并分析了作用机理.结果表明,改性三乙醇胺的助磨效果优于三乙醇胺,其中马来酸三乙醇胺盐的助磨增强效果最佳.