Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Sichuan, China.
Cancer Biol Ther. 2012 Nov;13(13):1244-54. doi: 10.4161/cbt.21460. Epub 2012 Aug 16.
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.
费城染色体阳性急性淋巴细胞白血病 (Ph+ ALL) 是由组成性激活的 BCR-ABL 和 SRC 家族酪氨酸激酶触发的。它们激活了多个生长信号通路，包括 Raf/MEK/ERK、Akt/mTOR 和 STAT5 通路。BCR-ABL 酪氨酸激酶抑制剂伊马替尼是 Ph+ 白血病的标准治疗方法，在 CML 中发挥有效作用。然而，伊马替尼对 SRC 酪氨酸激酶的抑制作用很小，与 CML 相比，Ph+ ALL 的反应率更低，复发更频繁、更快。先前的研究表明，冬凌草甲素可抑制多种肿瘤细胞的增殖并诱导其凋亡。然而，冬凌草甲素在 Ph+ ALL 中的抗癌活性和机制尚不清楚。为了研究冬凌草甲素的抗癌活性，我们研究了其在组成性激活的 Akt/mTOR、Raf/MEK/ERK、STAT5 和 SRC 通路、bcr/abl 基因的 mRNA 水平、细胞活力和 Ph+ ALL SUP-B15 细胞凋亡中的作用。此外，我们还检测了冬凌草甲素加伊马替尼的协同作用。结果表明，冬凌草甲素抑制 SRC 家族激酶之一 LYN 和 ABL 及其下游 Akt/mTOR、Raf/MEK/ERK 和 STAT5 通路的激活，下调 Bcl-2 但上调 Bax 蛋白，从而诱导 Ph+ ALL 细胞凋亡。冬凌草甲素加伊马替尼通过克服伊马替尼对 Akt/mTOR 和 LYN 信号的上调缺陷发挥协同作用。此外，我们还研究了冬凌草甲素对 Ph+ ALL 患者原代标本中信号通路的影响。结果表明，冬凌草甲素显著抑制这些原代标本中 Akt/mTOR、Raf/MEK 和 STAT5 通路的激活，并且冬凌草甲素加伊马替尼在一个伊马替尼耐药患者标本中对 mTOR、STAT5 和 LYN 信号具有协同抑制作用。进一步评估冬凌草甲素作为 Ph+ ALL 的潜在治疗药物似乎是合理的。
