Kinesiska forskare flyttar fram positionerna som presumtiva läkemedelsutvecklare. Här en studie som Oscar mejlat in till bloggen.Det handlar om Gliom,tumörer i hjärnan,som med dagens behandlingar strålning,kirurgi och ibland cytostatika ha visat sig ha låg effektivitet att få stopp på eländet innan gliomet utvecklats till en dödlig variant (malign). 2 årsöverlevnad vid användande mix av dessa behandlingar är i dagsläget inte bättre än 20%.Som de konstaterar inledningsvis i abstractet : Therefore, it is important to find novel drugs to effectively treat gliomas.Forskarna har alltså föresatt sig att hitta ett effektivt läkemedel mot denna förbannade best.De utgick från en beprövad läkemedelssubstans,Trametinib,som visat sig effektiv vid behandling av melanoma (hudcancer) metastaser.För att följa gliomceller vid tillsättande av olika styrkor av substansen från Trametinib använde forskarna sig av HoloMonitor och studerade utvecklingen över vissa tidsaxlar.6,12,24,48 och 72 timmar för att vara exakt.Med användande av HoloMonitor tillsammans med andra instrument kom de till följande slutsatser:
In conclusion, this study reveals a novel role of trametinib in inhibiting glioma cells. Trametinib inhibited the glycolysis level of glioma cells through the PKM2/c-myc pathway, and thus inhibited glioma cells to proliferate, migrate, and invade. At the molecular level, it was shown that the glycolysis level of trametinib on glioma cells is related to the PKM2/c-myc pathway. These results not only indicate the possible mechanism of trametinib in anti-tumor activity, but also reveal the therapeutic potential of trametinib on gliomas, which offers new insight for clinical drug development of gliomas.
Översatt blir det :
Sammanfattningsvis avslöjar denna studie en ny roll för trametinib när det gäller att hämma gliomceller. Trametinib hämmade glykolysnivån av gliomceller genom PKM2/c-myc-vägen och hämmade därmed gliomceller för att föröka sig, migrera och invadera. På molekylär nivå visades det att glykolysnivån för trametinib på gliomceller är relaterad till PKM2/c-myc-vägen. Dessa resultat indikerar inte bara den möjliga mekanismen för trametinib vid antitumöraktivitet, utan avslöjar också den terapeutiska potentialen för trametinib på gliom, vilket ger ny insikt för klinisk läkemedelsutveckling av gliom.
Studien som publicerades igår (21/10) är betitlad :
Trametinib Inhibits the Growth and Aerobic Glycolysis of Glioma Cells by Targeting the PKM2/c-Myc Axis
Gliomas are primary tumors originating from glial progenitor cells. Traditional treatments, including surgery, radiotherapy, and chemotherapy, have many limitations concerning the prognosis of patients with gliomas. Therefore, it is important to find novel drugs to effectively treat gliomas. Trametinib has been shown to inhibit the MAPK pathway and regulate its downstream extracellular-related kinases. It has widely been used in the treatment of BRAF V600E mutant metastatic melanomas. Previous studies found that trametinib can improve the prognosis of patients with melanoma brain metastases. In this study, we investigated the therapeutic effects of trametinib on gliomas in vivo and in vitro. We found that trametinib can inhibit proliferation, migration, and invasion of glioma cells, while inducing apoptosis of glioma cells. Specifically, trametinib can suppress both the expression of PKM2 in glioma cells and the transport of PKM2 into the cellular nucleus via suppression of ERK1/2 expression. However, inhibition of these cellular effects and intracellular glycolysis levels were reversed by overexpressing PKM2 in glioma cells. We also found inhibition of c-myc with trametinib treatment, but its expression could be increased by overexpressing PKM2. Interestingly, when PKM2 was overexpressed but c-myc silenced, we found that the initial inhibition of cellular effects and glycolysis levels by trametinib were once again restored. These inhibitory effects were also confirmed in vivo: trametinib inhibited the growth of the transplanted glioma cell tumor, whereas PKM2 overexpression and c-myc silencing restored the inhibition of trametinib on the growth of the transplanted tumor. In conclusion, these experimental results showed that trametinib may inhibit the growth and intracellular glycolysis of glioma cells by targeting the PKM2/c-myc pathway.
Introduction
Glioma is a highly malignant intracranial primary tumor, accounting for ∼60% of central nervous system tumors. Even if combined with surgery, radiotherapy, and chemotherapy, the 2-years survival rate is only 20%. Therefore, improving the curative effect and survival rate of patients with gliomas are major problems to solve (Zhang et al., 2018). Fortunately, finding a targeted killing therapy for glioblastomas is gradually becoming the core of anti-glioma therapy.
Trametinib is an inhibitor of MEK1/2, which regulates its downstream ERK kinases by inhibiting the MAPK pathway. In May 2013, the FDA approved the use of trametinib as a treatment for metastatic melanomas—and in addition, for lung cancer, renal cancer, thyroid cancer, cholangiocarcinoma, and breast cancer. Trametinib has also proven anti-tumor effects—either alone or in combination with other drugs (Bridgeman et al., 2016; Planchard et al., 2016; Davies et al., 2017; Ikeda et al., 2018; Subbiah et al., 2018). It has been confirmed that oral trametinib can improve the prognosis of patients with melanoma brain metastases, which suggests that an oral safe dose of trametinib can reach effective anti-melanoma therapeutic concentrations through the blood-brain barrier (Davies et al., 2017). Although there are few studies on the molecular mechanism of the anti-tumor effect of trametinib, recent clinical reports have confirmed its sole- or combination-use to produce safe and effective anti-glioma effects (Vander Heiden et al., 2009; Brown et al., 2017). However, no research has reported on its anti-tumor mechanism.
Ur studien (urval)
Cell Migration Assays
The HoloMonitor M4 culture system (PHIAB, Lund, Sweden) was used to detect the migration ability of glioma cells treated by trametinib. The trametinib treated cells were put into the system for 24 h, before being analyzed using the Hstudio M4 software.
FIGURE 1. Trametinib induces apoptosis of glioma cells and inhibit cell proliferation, migration, and invasion. (A) The toxic effect of trametinib on U87 cells. (B) The toxic effect of trametinib on U251. (C) U87 and U251 cells were treated with 50 nM trametinib for 0, 6, 12, 24, 48, and 72 h, and the effects of 50 nM trametinib on apoptosis were detected by flow cytometry. (D) Quantification of the apoptotic cells. (E) The migration ability of U87 and U251 cells was analyzed by Hstudio M4 system after 50 nM trametinib treatment for 0, 6, 12, 24, 48, and 72 h. Scale bars: 100 µm. (F) The invasion ability of glioma cells is detected by transwell assay after trametinib treatment for 0, 6, 12, 24, 48, and 72 h. Data are presented as means +SD (n = 3); *p < 0.05; **p < 0.01, vs control.
FIGURE 4. Trametinib inhibits migration, invasion, and glycolysis of glioma cells and induces apoptosis through PKM2. (A) PKM2 mRNA levels was measured in glioma cells transfected with a vector or PKM2. (B) Expression of c-myc, GLUT1 and LDHA by western blotting upon PKM2 overexpression after 50 nM trametinib treated for 48 h. (C) The effects of 50 nM trametinib treated for 48 h on apoptosis after PKM2 overexpression was detected by flow cytometry. (D) The capacity for migration in U87 and U251 cells on PKM2 overexpression after 50 nM trametinib treated for 48 h was analyzed by Hstudio M4 software. Scale bars: 100 µm. (E) The capacity for invasion in glioma cells on PKM2 overexpression after 50 nM trametinib treated for 48 h was detected by the transwell method. (F) ECAR indicates the level of aerobic glycolysis in glioma cells with PKM2 overexpression treated with 50 nM trametinib for 48 h. Data are presented as means +SD (n = 3); *p < 0.05; **p < 0.01, vs control. #p < 0.05; ##p < 0.01, vs Tra + vector group.
FIGURE 5. Trametinib regulates the killing effect and glycolysis level of glioma cells through PKM2/C-MYC axis. (A) trametinib (50 nM) for 48 h in glioma cells on the capacity for migration was analyzed by Hstudio M4 software. Scale bars: 100 µm. (B) trametinib (50 nM) for 48 h in glioma cells on the capacity for invasion was analyzed by transwell. (C) trametinib (50 nM) for 48 h in glioma cells on glycolysis was analyzed. (D) trametinib (50 nM) for 48 h in glioma cells on the levels of GLUT1 and LDHA was analyzed by western blotting. (E) trametinib (50 nM) for 48 h in glioma cells on expression of GLUT1 and LDHA was analyzed by qRT-PCR. Data are presented as means +SD (n = 3); *p < 0.05; **p < 0.01, vs control. #p < 0.05; ##p < 0.01, vs Tra + vector group. &p < 0.05; &&p < 0.01, vs Tra + PKM2+sh-NC group.
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