Apoptosis induction of human leukemia cells by Streptomyces sp. SY-103 metabolites through activation of caspase-3 and inactivation of Akt

Abstract

Abstract. We isolated 23 marine actinomycetes from seawater samples. Of these, strain SY-103 exhibited the strongest cytotoxic activity on human leukemic cell lines. Biochemical tests and 16S rDNA sequencing of this strain allowed us to identify SY-103 as a strain of the genus Streptomyces. In the present study, the pure cytotoxic compound (PCC) from Streptomyces sp. SY-103 metabolites was purified by reversephase HPLC and the biochemical mechanisms of PCCinduced apoptosis in cultured human leukemic cell lines were investigated. The exposure of cells to PCC resulted in growth inhibition and induction of apoptosis, which was associated with the proteolytic activation of caspase-3 and down-regulation of anti-apoptotic Bcl-2 protein. However, PCC-induced caspase-3 activation and apoptosis were significantly attenuated in Bcl-2 overexpressing U937 cells. z-DEVD-fmk, a caspase-3 specific inhibitor, blocked caspase-3 activation and increased the survival rate of PCC-treated U937 cells. The activity of Akt was also inhibited in PCC-treated cells, and phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor, LY294002, sensitized the cells to PCC-induced apoptosis indicating that the down-regulation of the Akt signaling pathway plays a key role in PCC-induced apoptosis. Our findings imply that some of the biological functions of Bcl-2 and PI3K/Akt are attributed to their ability to inhibit PCC-induced apoptosis; therefore, it is suggested that this compound is a promising anti-cancer agent for leukemia cells.

Synthesis, in vitro cytotoxic and apoptotic effects, and molecular docking study of novel adamantane derivatives

“…Moreover, this sequential cascade triggers several proteases including caspase-1, -3, and -9. [44][45][46] Caspase-3 (CASP3) also activates the pathway of several enzymatic events and serves as the promoter of apoptosis. [47] In the present study, compounds 4a and 4c induced p53 and BAX gene expression and decreased expression levels of BCL2;…”

Streptomyces Levis ABRIINW111 Inhibits SW480 Cells Growth by Apoptosis Induction

“…SY-103 have strong cytotoxic effects which induce apoptosis in human leukemia cells through the activation of caspase3 and inactivation of Akt signaling. 10,11 Recently, it was indicated that ether extracted metabolites of Streptomyces Levis ABRIINW111 have anti-carcinogenic effects on colon cancer 12 as well. Apoptosis was used as a target for cancer therapy and several drugs were designed to activate Caspase family.…”