Oridonin in combination with imatinib exerts synergetic anti-leukemia effect in Ph+ acute lymphoblastic leukemia cells in vitro by inhibiting activation of LYN/mTOR signaling pathway

Abstract

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.

Synergistic anticancer effects of combined γ-tocotrienol and oridonin treatment is associated with the induction of autophagy

“…Studies have shown that ctocotrienol is a potent inhibitor of PI3K/Akt/mTOR signaling pathway, and cancer cells are more sensitive to this effect than the normal cells [5,7,45]. Oridonin has also been reported to suppress Akt/mTOR signaling pathway in other types of cancer cells [47,48]. Findings in the present study show that the synergistic anticancer effects of combined c-tocotrienol and oridonin treatment is associated with a large inhibition in PI3K/Akt/mTOR signaling.…”

Curcumin potentiates the anti-leukemia effects of imatinib by downregulation of the AKT/mTOR pathway and BCR/ABL gene expression in Ph+ acute lymphoblastic leukemia

“…Further studies have shown that imatinib treatment increased the activations of AKT/mTOR signaling. Additionally, imatinib had little effect on the activation of LYN kinase, one of SRC kinases (Guo et al, 2012). Thus, we hypothesized that aberrant signaling from the AKT/mTOR and LYN kinase pathways may account for the poor response of Ph+ ALL to imatinib, at least partially, and that they may be the underlying basis of imatinib resistance.…”

Effects of Oridonin on Hepatic Cytochrome P450 Expression and Activities in PXR-Humanized Mice

“…29,30) The present study may provide at least part of the evidence for oridonin-drug interactions for the up-regulation of oridonin on the hepatic drug metabolizing system.…”