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المؤلفPrabhu K.S.
المؤلفSiveen K.S.
المؤلفKuttikrishnan S.
المؤلفJochebeth A.
المؤلفAli T.A.
المؤلفElareer N.R.
المؤلفIskandarani A.
المؤلفKhan A.Q.
المؤلفMerhi M.
المؤلفDermime S.
المؤلفEl-Elimat T.
المؤلفOberlies N.H.
المؤلفAlali F.Q.
المؤلفSteinhoff M.
المؤلفUddin S.
تاريخ الإتاحة2020-04-16T06:56:45Z
تاريخ النشر2019
اسم المنشورBiomolecules
المصدرScopus
الرقم المعياري الدولي للكتاب2218273X
معرّف المصادر الموحدhttp://dx.doi.org/10.3390/biom9040126
معرّف المصادر الموحدhttp://hdl.handle.net/10576/14202
الملخصGreensporone 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.
راعي المشروعQatar University , University of North Carolina, National Palliative Care Research Center, Jordan University of Science and Technology
اللغةen
الناشرMDPI AG
الموضوعAKT
Apoptosis
cIAP
Greensporone A
Imatinib
Reactive oxygen species
العنوانGreensporone A, a fungal secondary metabolite suppressed constitutively activated AKT via ROS generation and induced apoptosis in leukemic cell lines
النوعArticle
رقم العدد4
رقم المجلد9
dc.accessType Open Access


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