Greensporone A, a Fungal Secondary Metabolite Suppressed Constitutively Activated AKT via ROS Generation and Induced Apoptosis in Leukemic Cell Lines

Abstract

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.

Isoliensinine induces cervical cancer cell cycle arrest and apoptosis by inhibiting the AKT/GSK3α pathway

“…During the dose selection of AKTi-1/2, only observation of cell death at the corresponding doses was used in the methodology, which is a limitation of the present study. A previous study found that AKTi-1/2 can induce cell apoptosis by downregulating Mcl-1 expression in leukemic cells ( 34 ). Therefore, the mechanism by which isoliensinine induces apoptosis in cervical cancer cells may be similar to that by AKTi-1/2.…”

Freshwater Fungi as a Source of Chemical Diversity: A Review

“…(strain S1a1) was isolated. A chemical study of the ethyl acetate extract of a solid rice medium culture yielded three new [penitanzchroman (114) and tanzawaic acids Y (115) and Z (116)] and six known tanzawaic acid derivatives [arohynapene A (117) and tanzawaic acids A (118), B (119), E (120), M (121), and N (122)], three isochromans [(3S)-6-hydroxy-8-methoxy-3,5dimethylisochroman (123), (3S,4R)-6-hydroxy-8-methoxy-3,5-dimethylisochromanol (124), and (1S,3S)-1,6-dihydroxy-3,5-dimethyl-8-methoxyisochroman (125)], and two benzoquinones [anserinones A (126) and B (127)]. 139 Furthermore, investigation of the same fungus using the OSMAC (one-strain many-compounds) approach 140 afforded tanzawaic acid Z1 (128).…”

“…While preparing this manuscript, the total synthesis of compounds 21 and 22 was achieved and the absolute configuration of the stereogenic centers of the tetrahydrofuran rings was established as (5 R ,8 R ) . In a set of pharmacological evaluations, greensporones A ( 10 ) and C ( 14 ) were found to suppress the growth of leukemic cells via induction of apoptotic cell death. , An additional point about this particular example is that there was nothing remarkable about the collection of the fungus. Members of our team were simply demonstrating collecting techniques to a group of students, and yet, a species was isolated that yielded a suite of 14 new resorcylic acid lactones.…”

Novel Steroidal 5α,8α-Endoperoxide Derivatives with Semicarbazone/Thiosemicarbazone Side-chain as Apoptotic Inducers through an Intrinsic Apoptosis Pathway: Design, Synthesis and Biological Studies

“…Washed the obtained pellet with PBS and centrifuged for 3 min. A last, of PBS (400 µL) was added and analyzed by flow cytometer (BD Biosciences, San Jose, CA, USA) [43].…”