Abstract
Burkitt’s lymphoma (BL) is a highly aggressive malignancy molecularly characterized by deregulation of the C-MYC proto-oncogene. Recently, it has been confirmed that phosphatidylinositol-3-kinase (PI3K) pathway activation is a crucial element in the malignant transformation of the B cells in BL. Despite the better outcome of adults with BL treated with high-intensity chemotherapy regimens, the overall survival rate for patients older than 60 years remains dismal. Shikonin, a natural naphthoquinone derived from Chinese herbal medicine plant, has the potential to induce cell death in a series of human cancer. In the present study, we investigated the effect and molecular mechanisms of Shikonin in treatment with BL. Shikonin suppressed cellular proliferation and induced caspase-dependent apoptosis in BL cells. Inhibition of C-MYC and suppression of PI3K/AKT/mTOR pathway played critical roles in SHK-induced apoptosis in BL both in vitro and in vivo. Besides, Shikonin potentiated doxorubicin-induced growth inhibition and apoptosis in vitro. Furthermore, the growth of a subcutaneous xenograft tumor model of BL was significantly inhibited by shikonin. Importantly, we did not find the effect of shikonin on liver function in mice. In summary, these data suggest that shikonin may be an encouraging chemotherapeutic agent in the clinical treatment of BL.
Highlights
Burkitt’s lymphoma (BL) is a highly aggressive malignancy derived from germinal center B cells, with a cellular doubling time of 25 hours[1]
These results demonstrate that C-MYC and PI3K pathway have emerged as promising therapeutic targets in BL
The results showed that SHK suppressed cellular proliferation and induced caspase-dependent apoptosis through inhibition of the expression of C-MYC and the modulation of PI3K signaling in BL cells
Summary
Burkitt’s lymphoma (BL) is a highly aggressive malignancy derived from germinal center B cells, with a cellular doubling time of 25 hours[1]. C-MYC contributes to the activation of the PI3K pathway by promoting expression of mir-17–92 cluster, one of which decreases expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN)[9]. Overall, these results demonstrate that C-MYC and PI3K pathway have emerged as promising therapeutic targets in BL. The anti-tumor activity of SHK may involve in its ability to generate reactive oxygen species[12], activate pro-apoptotic caspase family members, inhibit the expression of C-MYC13 and suppress PI3K phosphorylation[14]. The results showed that SHK suppressed cellular proliferation and induced caspase-dependent apoptosis through inhibition of the expression of C-MYC and the modulation of PI3K signaling in BL cells. The present data suggest that SHK may serve as a novel agent for the treatment of BL because of its likely targets
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