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.