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.
Highlights
Cancer is one of the prime causes of mortality and accounts for nearly 13% of deaths worldwide.The World Health Organization estimates that there might be 21.4 million cases of cancer and nearly13.2 million deaths from cancer annually by 2030 [1]
To examine whether or not greensporone A had any effect on cell viability status of leukemic cell lines, we treated leukemic cell lines (K562, U937, and AR230) with and without greensporone A for 24 h analyzed their cell proliferation capacity using Cell Counting Kit-8 (CCK-8)
We have investigated the anti-proliferative activity of two resorcyclic acid lactone greensporone A and greensporone C in leukemic cell lines
Summary
Cancer is one of the prime causes of mortality and accounts for nearly 13% of deaths worldwide.The World Health Organization estimates that there might be 21.4 million cases of cancer and nearly13.2 million deaths from cancer annually by 2030 [1]. Cancer is one of the prime causes of mortality and accounts for nearly 13% of deaths worldwide. The World Health Organization estimates that there might be 21.4 million cases of cancer and nearly. 13.2 million deaths from cancer annually by 2030 [1]. Leukemia is a form of cancer in which white blood cells and their precursors dominate and differentiate abnormally, leading to suppression of production and functioning of healthy cells. The standard therapeutic strategies for cancer include chemotherapy, surgery, and radiation. The foremost problem in chemotherapy is the development of a cancer resistance mechanism, due to up-regulation of multi-drug resistance protein (MDR) and a decrease in the rate of apoptotic proteins [2]. Since the majority of chemotherapeutic treatments are associated with severe adverse effects, alternative forms of treatment using natural products are considered as a promising area of research [3]
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