The Critical Role of PTEN/PI3K/AKT Signaling Pathway in Shikonin-Induced Apoptosis and Proliferation Inhibition of Chronic Myeloid Leukemia

Abstract

Background/Aims: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm. Tyrosine kinase inhibitors (TKIs) are commonly used to treat CML; however, drug resistance of CML cells to TKIs has limited their clinical application. Shikonin, a traditional Chinese herb, has long been used to treat leukemia in China, but the roles and related molecular mechanisms of shikonin treatment in CML remain unclear. Here, we aimed to evaluate the effects of shikonin on the proliferation, apoptosis, and migration of K562 cells, a CML cell line. Methods: Firstly, K562 cell proliferation and apoptosis were tested by CCK8 assay and flow cytometry with Annexin V-FITC/PI staining. Cell migration was measured by Transwell migration assay. In addition, western blot was performed to determine the proteins (PI3K, Bax, Bcl-2, cleaved caspase-3, PTEN, p-AKT, AKT, CXCR4, SDF-1, CD44) involved in the mechanism of action of shikonin. Finally, neutrophils from peripheral blood of CML patients were obtained, and cell proliferation and apoptosis were tested by CCK8 assay and flow cytometry. Results: Shikonin reduced the proliferation of K562 cells in a time- and dose-dependent manner and promoted the apoptosis of K562 cells. Moreover, shikonin increased the PTEN level and inactivated the PI3K/AKT signaling pathway, subsequently upregulating BAX in K562 cells. In addition, shikonin could block K562 cell migration via the CXCR4/SDF-1 axis. Finally, shikonin significantly inhibited the proliferation and promoted the apoptosis of neutrophils from CML patients. Conclusion: These results demonstrated that shikonin inhibits CML proliferation and migration and induces apoptosis by the PTEN/PI3K/AKT pathway, revealing the effects of shikonin therapy on CML.

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…Shikonin induces apoptosis and inhibits metastasis through suppressing ERK pathway in human NSCLC NCI-H460 and A549 cells, respectively [611,617]. c-Myc down-regulation along with inhibition of ERK/JNK/ MAPK and Akt pathways are also involved in shikonininduced apoptosis and anti-proliferation in acute and chronic leukemia [618][619][620]. Moreover, the activation of necroptosis initiators, receptor interacting serine-threonine protein kinase (RIP) 1 and RIP3, by shikonin does not only contribute to DNA double strand breaks via ROS overproduction [621], but also facilitates glycolysis suppression via intracellular H 2 O 2 production [622].…”

Design, synthesis and anticancer activity of naphthoquinone derivatives

“…Inducing autophagy is also one of the main mechanisms for anti-cancer activity 13,22,23 . Among them, PI3K and mTOR signalling pathways have been proved to be the main signal pathways to regulate autophagy [24][25][26][27] . However, for these kinds of derivatives, the poor selectivity and high cytotoxicity limit their clinical application.…”

<p>Experimental Study of Hepatocellular Carcinoma Treatment by Shikonin Through Regulating PKM2</p>

“…25 By regulating the PI3K/Akt signaling pathway, shikonin exerts anti-tumor effects in non-small cell lung cancer, chronic granulocyte leukemia, and Burkitt's lymphoma. [26][27][28] In the present study, we investigated the anti-tumor effects of SK in HCC cells. Our results showed that SK significantly inhibited HCC cell proliferation and glycolysis, and promoted HCC cell apoptosis.…”