Philadelphia chromosome-positive
acute lymphoblastic leukemia (Ph+ ALL) is triggered by constitutively activated BCR-ABL and
SRC family tyrosine kinases.They account for the activations of multiple growth-signaling pathways, including Raf/
MEK/ERK, Akt/mTOR and STAT5 pathways. The
BCR-ABL tyrosine kinase inhibitor
imatinib is the standard treatment for Ph+
leukemia and plays efficacious role in CML. However,
imatinib has few inhibitory effects on
SRC tyrosine kinase with response rate of Ph+ ALL lower and relapse more frequent and quicker compared with CML. Previous studies showed that
oridonin inhibits proliferation and induces apoptosis in many
tumor cells. However, the anticancer activity and mechanism of
oridonin in Ph+ ALL is unknown. To investigate the anticancer activity of
oridonin, we examined its role in constitutively activated Akt/mTOR, Raf/
MEK/ERK, STAT5 and SRC pathway,
mRNA level of bcr/abl gene, cell viability and apoptosis in Ph+ ALL SUP-B15 cells. Furthermore, we detected synergetic effect of
oridonin plus
imatinib. Our results showed that
oridonin inhibiting activations of LYN (one of
SRC family kinases) and ABL and their downstream Akt/mTOR, Raf/
MEK/ERK and STAT5 pathways, downregulated Bcl-2 but upregulated
Bax protein and then induced apoptosis in Ph+ ALL cells.
Oridonin plus
imatinib exerted synergetic effects by overcoming
imatinib defect of upregulating Akt/mTOR and LYN signaling. Additionally, we examined the effect of
oridonin on the signaling pathways in the primary specimens from Ph+ ALL patients. Our data showed that
oridonin remarkably suppressed activations of Akt/mTOR, Raf/
MEK and STAT5 pathway in these primary specimens and
oridonin with
imatinib exerted synergetic suppressive effects on mTOR, STAT5 and LYN signaling in one
imatinib resistant patient specimen. Additional evaluation of
oridonin as a potential therapeutic agent for Ph+ ALL seems warranted.