Cryptotanshinone inhibits human glioma cell proliferation in vitro and in vivo through SHP-2-dependent inhibition of STAT3 activation

Abstract

Malignant gliomas (MGs) are one of the most common primary brain cancers in adults with a high mortality rate and relapse rate. Thus, finding better effective approaches to treat MGs has become very urgent. Here, we studied the effects of cryptotanshinone (CTS) on MGs in vitro and in vivo, and explored the underlying mechanisms. Effects of CTS in vitro on cell proliferation, cycle, migration and invasion were evaluated. The activation of JAK/STATs signaling was detected by western blot and immunofluorescenc staining. SHP-2 inhibitor or SiRNA were used to determine the involvement of SHP-2. The in vivo anti-MGs activity of CTS was studied with nude mice bearing intracerebral U87 xenografts. Our results revealed that CTS significantly inhibited the proliferation of MGs in vitro via inhibiting STAT3 signal pathway. The cell cycle was arrested at G0/G1 phase. Although CTS did not change the expression of total SHP-2 protein, the tyrosine phosphatase activity of SHP-2 protein was increased by CTS treatment in a dose-dependent manner in vivo and in vitro. SHP-2 inhibitor or SiRNA could reverse the inhibitory effect of CTS on phosphorylation of STAT3 Tyr705. In vivo study also showed that CTS inhibited the intracranial tumor growth and extended survival of nude mice bearing intracerebral U87 xenografts, confirming an inhibitory effect of CTS on MGs. Our results indicated CTS may be a potential therapeutic agent for MGs. The inhibitory action of CTS is largely attributed to the inhibition of STAT3 Tyr705 phosphorylation with a novel mechanism of upregulating the tyrosine phosphatase activity of SHP-2 protein.

Cryptotanshinone suppresses cell proliferation and glucose metabolism via STAT3/SIRT3 signaling pathway in ovarian cancer cells

“…Cryptotanshinone (CT) is isolated from the plant Salvia miltiorrhiza Bunge and has been identified to block STAT3 phosphorylation and homodimerization . CT has been demonstrated to have anti‐tumor activities in various malignancies, including breast cancer,liver cancer,prostate cancer, and ovarian cancer .…”

“…Cryptotanshinone (CT) is isolated from the plant Salvia miltiorrhiza Bunge and has been identified to block STAT3 phosphorylation and homodimerization. [7][8][9] CT has been demonstrated to have anti-tumor activities in various malignancies, including breast cancer,liver cancer,prostate cancer, and ovarian cancer. [10][11][12][13] CT was found to induced apoptosis and cell cycle arrest in gastric cancer cells via reactive oxygen species (ROS)-mediated MAPK and AKT signaling pathways.…”

In vitro assays and techniques utilized in anticancer drug discovery

“…Dai et al (2017) have used the BrdU assay to examine the antiproliferative efficacy of isocostunolide in glioma stem cells. Lu et al (2017) have used the BrdU assay to determine cryptotanshinone-mediated cell proliferation in human glioma cells (U 251). As BrdU is a toxic substance, care must be taken when handling (Miller & Nowakowski, 1988).…”

Comprehensive Live-cell Imaging Analysis of Cryptotanshinone and Synergistic Drug-Screening Effects in Various Human and Canine Cancer Cell Lines

“…Other benefits of Salvia miltiorrhiza include antibacterial (23), immunomodulatory (24) and antioxidant (25) activities. One of the main components of Salvia miltiorrhiza, Cryptotanshinone (CT), has been evaluated in vitro and in vivo as anticancer treatment in human tumor cell lines from different origins, such as, prostate (18,26), breast (26,27,28,29) hepatic (30) and colorectal (18,30,31,32), lung (33), pancreatic (34), kidney (35), glioma (36) and ovarian (37). To date, several human studies have highlighted significant apoptotic effects of CT treatment in cancer cell lines using concentrations of 5 -50 μM (28,32,33,34).…”

“…To date, several human studies have highlighted significant apoptotic effects of CT treatment in cancer cell lines using concentrations of 5 -50 μM (28,32,33,34). Other effects of CT included cell cycle arrest at G1/G0 phase (30,34,38), and at G2/M phase (33,36,39), inhibition of Cyclin D1 protein expression in different types of cancer (18,31,33,34,35), and downregulation of matrix metallopeptidases (MMP-2/MMP-9), which are responsible for cell invasion and metastasis (37). Human cancer cells exposed to different concentrations of CT showed inhibition of major signaling pathways that are involved in multiple cellular processes such as, mammalian target of rapamycin (mTOR) in hepatic (30), gastric (30), pancreatic (34), soft sarcoma (38) and prostate (38) cancer.…”