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Resorcylic acid lactones (RALs) are fungal polyketides that consist of a β-resorcylic acid residue (2,4-dihydroxybenzoic acid) embedded in a macrolactone ring. RALs exhibit a broad range of biological activities, including anticancer activities. Following discovery of the selective Hsp90 inhibition activity of radicicol, the kinase inhibition activity of hypothemycin, monocillin II, 5Z-7-oxo-zeaenol, and L-783,277 RALs, and the nuclear factor kappa B (NF-κB) inhibition activity of the RAL zearalenone, have attracted great attention as potential therapeutics for cancer treatment. In this minireview, we focus on natural RALs that possess cytotoxic activities [IC50 values

Karem H Alzoubi,1,* Laila Abdel-Hafiz,2,3,* Omar F Khabour,4 Tamam El-Elimat,3 Mohammad A Alzubi,5 Feras Q Alali6,7 1Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan; 2Institute of Anatomy II, Medical Faculty, Heinrich Heine Universität, Düsseldorf, Germany; 3Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan; 4Department of Medical Laboratory Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan; 5Integrative Life Sciences Doctoral Program, Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA; 6College of Pharmacy, QU Health, Qatar University, Doha Qatar; 7Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar*These authors contributed equally to this workCorrespondence: Feras Q AlaliCollege of Pharmacy, Qatar University, Doha 2713, QatarEmail Feras.alali@qu.edu.qaBackground: Chronic psychosocial stress impairs memory function and leads to a depression-like phenotype induced by a persistent status of oxidative stress. Hypericum perforatum L. (St. John’s wort) is widely used to relieve symptoms of anxiety and depression; however, its long-term use is associated with adverse effects. Hypericum triquetrifolium Turra is closely related to H. perforatum. Both plants belong to Hypericaceae family and share many biologically active compounds. Previous work by our group showed that methanolic extracts of H. triquetrifolium have potent antioxidant activity as well as high hypericin content, a component that proved to have stress-relieving and antidepressant effects by other studies. Therefore, we hypothesized that H. triquetrifolium would reduce stress-induced cognitive impairment in a rat model of chronic stress.Objective: To determine whether chronic treatment with H. triquetrifolium protects against stress-associated memory deficits and to investigate a possible mechanism.Methods: The radial arm water maze (RAWM) was used to test learning and memory in rats exposed to daily stress using the resident–intruder paradigm. Stressed and unstressed rats received chronic H. triquetrifolium or vehicle. We also measured levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, cortex and cerebellum.Results: Neither chronic stress nor chronic H. triquetrifolium administration affected performance during acquisition. However, memory tests in the RAWM showed that chronic stress impaired different post-encoding memory stages. H. triquetrifolium prevented this impairment. Furthermore, hippocampal BDNF levels were markedly lower in stressed animals than in unstressed animals, and chronic administration of H triquetrifolium chronic administration protected against this reduction. No significant difference was observed in the effects of chronic stress and/or H. triquetrifolium treatment on BDNF levels in the cerebellum and cortex.Conclusion: H. triquetrifolium extract can oppose stress-associated hippocampus-dependent memory deficits in a mechanism that may involve BDNF in the hippocampus.Keywords: Hypericum triquetrifolium, methanolic extract, stress, learning, memory, hippocampus, BDNF

Greensporone A is a fungal secondary metabolite that has exhibited potential in vitro for anti-proliferative activity in vitro. We studied the anticancer activity of greensporone A in a panel of leukemic cell lines. Greensporone A-mediated inhibition of proliferation is found to be associated with the induction of apoptotic cell death. Greensporone A treatment of leukemic cells causes inactivation of constitutively activated AKT and its downstream targets, including members GSK3 and FOXO1, and causes downregulation of antiapoptotic genes such as Inhibitor of Apoptosis (IAPs) and Bcl-2. Furthermore, Bax, a proapoptotic member of the Bcl-2 family, was found to be upregulated in leukemic cell lines treated with greensporone A. Interestingly, gene silencing of AKT using AKT specific siRNA suppressed the expression of Bcl-2 with enhanced expression of Bax. Greensporone A-mediated increase in Bax/Bcl-2 ratio causes permeabilization of the mitochondrial membrane leading to the accumulation of cytochrome c in the cytoplasm. Greensporone A-induced cytochrome c accumulation causes the activation of caspase cascade and cleavage of its effector, poly(ADP-ribose) polymerase (PARP), leading to apoptosis. Greensporone A-mediated apoptosis in leukemic cells occurs through the generation of reactive oxygen species (ROS) due to depletion of glutathione (GSH) levels. Finally, greensporone A potentiated the anticancer activity of imatinib in leukemic cells. In summary, our study showed that greensporone A suppressed the growth of leukemic cells via induction of apoptotic cell death. The apoptotic cell death occurs by inhibition of AKT signaling and activation of the intrinsic apoptotic/caspase pathways. These results raise the possibility that greensporone A could be developed as a therapeutic agent for the treatment of leukemia and other hematological malignancies.