Stellettin B induces apoptosis in human chronic myeloid leukemia cells via targeting PI3K and Stat5

Abstract

Novel agents are still urgently expected for therapy of chronic myeloid leukemia (CML). The in vitro anti-leukemia activity of Stellettin B (Stel B), a triterpenoid we isolated from marine sponge Jaspis stellifera, on human CML K562 and KU812 cells was recently investigated. Stel B inhibited K562 and KU812 cell proliferation with IC50 as 0.035 μM and 0.95 μM respectively. While no obvious cell cycle arrest was observed, apoptosis was induced in K562 cells after Stel B treatment. The Stel B-induced apoptosis might be in mitochondrial pathway, with increase of Bad and Bax, decrease of Bcl-2 and activation of caspase-9. In addition, dose-dependent increase of reactive oxygen species (ROS) and loss of mitochondrial membrane potential (MMP) occurred. Meanwhile, Stel B inhibited phosphorylation of Stat5, expression of 4 PI3K catalytic isoforms, and phosphorylation of the downstream effectors including PDK1 and Akt, suggesting that inhibition against Stat5 and PI3K might be involved in the apoptosis-inducing effect. Combination of Stel B with Imatinib with ratio as IC50 Stel B: 5×IC50 Imatinib led to synergistic effect. Stel B might become a promising candidate for CML therapy alone or together with Imatinib.

Aurantoside C Targets and Induces Apoptosis in Triple Negative Breast Cancer Cells

“…The ability of C828 in inhibiting the phosphorylation of Akt/mTOR and NF-κB pathways is particularly relevant as TNBC has constitutive activation of these pathways [ 10 , 11 , 17 ], which favors metastatic processes and chemo-resistance mechanisms [ 16 , 18 ]. Our result are in agreement with those reported for stellettin B, a triterpene that was derived from marine sponge Jaspis stellifera inhibited proliferation and induced cell death in human non-small cell lung cancer, human chronic myeloid leukemia and human glioblastoma cancer cells by inhibiting Akt/mTOR signaling pathways [ 68 , 69 , 70 ]. Moreover, it is known that the upregulation of Akt and NF-κB signaling pathways is related to the activation of cyclin D1 that leads to proliferation of cancer cells [ 21 , 71 ] and decline in CDKI, p21, thus inhibiting apoptosis [ 72 , 73 , 74 , 75 , 76 , 77 ].…”

Marine Sponge Natural Products with Anticancer Potential: An Updated Review

“…In all four cell lines, Stellettin B induced an increase in the reactive oxygen species (ROS) levels that was linked to apoptosis. In leukemia cells, it triggered the mitochondrial pathway through upregulation of Bak and Bax protein levels, downregulation of Bcl-2, and induction of MOMP [ 46 ]. In SF295 and A549 cell lines, the pathway was not investigated [ 48 ].…”

“…More recently, Chen et al [ 47 ] and Wang et al [ 48 ] confirmed Stellettin B’s ability to trigger apoptosis via Akt inhibition in A549, K562 and KU812 cells. However, as opposed to the evidence on glioblastoma cells, the authors showed the inhibition of the expression of p110, the catalytic subunit of PI3K, and the phosphorylation of phosphoinositide-dependent kinase-1 (PDK1), another Akt upstream protein [ 46 , 47 ]. An interesting experiment would be to evaluate the PDK1 levels in Stellettin B-treated SF295 cells.…”

“…An interesting experiment would be to evaluate the PDK1 levels in Stellettin B-treated SF295 cells. In the leukemic cell lines, Stellettin B inhibited Stat5 phosphorylation, a PI3K upstreaming protein, increasing the evidence that PI3K/Akt is involved in its cytotoxic mechanism [ 46 ]. In both leukemia and lung cancer cells, the expression of Akt downstream proteins were investigated after Stellettin B treatment, and a decrease in mTOR, a negative modulator of autophagy, was recorded, suggesting a role of this process in the potential antitumor activity of this sponge derivative [ 46 , 47 ].…”

Marine sponges of the genus Stelletta as promising drug sources: chemical and biological aspects

“…The most recent biological research on stellettin B was reported by Kong and co-workers 104 in 2017. They investigated in vitro anti-leukemia activity of stellettin B on human CML K562 and KU812 cells.…”