Current and future therapeutic strategies for high-grade gliomas leveraging the interplay between epigenetic regulators and kinase signaling networks.

Targeted therapies, including small molecule inhibitors directed against aberrant kinase signaling and chromatin regulators, are emerging treatment options for high-grade gliomas (HGG). However, when translating these inhibitors into the clinic, their efficacy is generally limited to partial and transient responses. Recent studies in models of high-grade gliomas reveal a convergence of epigenetic regulators and kinase signaling networks that often cooperate to promote malignant properties and drug resistance. This review examines the interplay between five well-characterized groups of chromatin regulators, including the histone deacetylase (HDAC) family, bromodomain and extraterminal (BET)-containing proteins, protein arginine methyltransferase (PRMT) family, Enhancer of zeste homolog 2 (EZH2), and lysine-specific demethylase 1 (LSD1), and various signaling pathways essential for cancer cell growth and progression. These specific epigenetic regulators were chosen for review due to their targetability via pharmacological intervention and clinical relevance. Several studies have demonstrated improved efficacy from the dual inhibition of the epigenetic regulators and signaling kinases. Overall, the interactions between epigenetic regulators and kinase signaling pathways are likely influenced by several factors, including individual glioma subtypes, preexisting mutations, and overlapping/interdependent functions of the chromatin regulators. The insights gained by understanding how the genome and epigenome cooperate in high-grade gliomas will guide the design of future therapeutic strategies that utilize dual inhibition with improved efficacy and overall survival.

Evaluating the Antiparasitic Activity of Novel BPZ Derivatives Against Toxoplasma gondii.

Prevalence studies revealed that one-third of the human population is chronically infected with Toxoplasma gondii. Presently, such infections are without medical treatment that effectively eradicates the parasite once it is in its latent form. Moreover, the therapeutics used to treat acute infections are poorly tolerated by patients and also cause the parasite to convert into long-lasting tissue cysts. Hence, there is a dire need for compounds with antiparasitic activity against all forms of T. gondii. This study examines the antiparasitic capacity of nine novel bisphenol Z (BPZ) derivatives to determine whether they possessed any activity that prevented T. gondii replication. To begin assessing the efficacy of the novel derivatives, parasites were treated with increasing concentrations of the compounds, then doubling assays and MitoTracker staining were performed. Three of the nine compounds demonstrated strong inhibitory activity, i.e., parasite replication significantly decreased with higher concentrations. Additionally, many of the treated parasites exhibited decreases in fluorescent signaling and disruption of mitochondrial morphology. These findings suggest that bisphenol Z compounds disrupt mitochondrial function to inhibit parasite replication and may provide a foundation for the development of new and effective treatment modalities against T. gondii.

Design, synthesis, and biological evaluation of lipophilically modified bisphenol Z derivatives.

In the present study, a small library of bisphenol Z (BPZ) derivatives was synthesized and investigated for anti-proliferative effects in cultured breast and glioblastoma cell lines. Synthesized BPZ derivatives varied in molecular size, polarity, and lipophilicity. Of the 8 derivatives tested, compounds 4 and 6, both of which displayed the highest degree of lipophilicity, were most active at inducing cell death as determined by the XTT assay. Cell membranes were interrogated using trypan blue staining and were shown to remain intact during treatments with 4 and 6. Activation of caspase enzymes (3 and/or 7) was noted to occur following treatment with compound 4. Polar BPZ derivatives, those with a substituted amine or alcohol, were devoid of any inhibitory or proliferative effects. The remaining derivatives seem to lack sufficient lipophilicity to execute an overt toxic effect. Our results suggest that increasing the lipophilic character of BPZ enhances the cytotoxic effects.

Fatty acylation enhances cellular localization of dansylated phenylalanines.

Two series of fluorescent molecules were synthesized by acylation of dansyl ethylenediamine and phenylalanine dansyl ethylenediamine with one of either acetyl (C(2)), hexanyl (C(6)), cyclohexanecarbonyl (C(7)), myristyl (C(14)), or palmityl (C(16)) groups and examined for entry and localization in Chinese Hamster Ovary (CHO) cells in tissue culture. Gross total fluorescence retention and cellular microscopic fluorescence patterns were analyzed. In both series, molecules with myristyl or palmityl groups entered cells. Only in the phenylalanine series did hexyl and cyclohexanecarbonyl modification enable entry. Consistent with a mechanism of passive diffusion, entry of compounds into cells was neither energy dependent nor endocytosis linked. Acylated molecules were observed to localize in cytoplasm and not enter nuclei or associate with lipophilic plasma membranes.