Vitamin K1 enhances sorafenib-induced growth inhibition and apoptosis of human malignant glioma cells by blocking the Raf/MEK/ERK pathway
Tóm tắt
The combined effects of anticancer drugs with nutritional factors against tumor cells have been reported previously. This study characterized the efficacy and possible mechanisms of the combination of sorafenib and vitamin K1 (VK1) on glioma cell lines. We examined the effects of sorafenib, VK1 or their combination on the proliferation and apoptosis of human malignant glioma cell lines (BT325 and U251) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry and 4′,6-diamidino-2-phenylindole (DAPI) assay. The signaling pathway changes were detected by western blotting. Sorafenib, as a single agent, showed antitumor activity in a dose-dependent manner in glioma cells, but the effects were more pronounced when used in combination with VK1 treatment. Sorafenib in combination with VK1 treatment produced marked potentiation of growth inhibition and apoptosis, and reduced expression of phospho-mitogen-activated protein kinase kinase (MEK) and phospho-extracellular signal-regulated kinase (ERK). Furthermore, the expression levels of antiapoptotic proteins Bcl-2 and Mcl-1 were significantly reduced. Our findings indicated that VK1 enhanced the cytotoxicity effect of sorafenib through inhibiting the Raf/MEK/ERK signaling pathway in glioma cells, and suggested that sorafenib in combination with VK1 maybe a new therapeutic option for patients with gliomas.
Tài liệu tham khảo
Sathornsumetee S, Reardon DA, Desjardins A, Quinn JA, Vredenburgh JJ, Rich JN: Molecularly targeted therapy for malignant glioma. Cancer. 2007, 110: 13-24. 10.1002/cncr.22741.
Hadziahmetovic M, Shirai K, Chakravarti A: Recent advancements in multimodality treatment of gliomas. Future Oncol. 2011, 7: 1169-1183. 10.2217/fon.11.102.
Das G, Shiras A, Shanmuganandam K, Shastry P: Rictor regulates MMP-9 activity and invasion through Raf-1-MEK-ERK signalingpathway in glioma cells. Mol Carcinog. 2011, 50: 412-423. 10.1002/mc.20723.
Goillot E, Raingeaud J, Ranger A, Tepper RI, Davis RJ, Harlow E, Sanchez I: Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway. Proc Natl Acad Sci USA. 1997, 94: 3302-3307. 10.1073/pnas.94.7.3302.
Du K, Zheng Q, Zhou M, Zhu L, Ai B, Zhou L: Chlamydial antiapoptotic activity involves activation of the Raf/MEK/ERK survival pathway. Curr Microbiol. 2011, 63: 341-346. 10.1007/s00284-011-9985-2.
Lo HW: Targeting Ras-RAF-ERK and its interactive pathways as a novel therapy for malignant gliomas. Curr Cancer Drug Targets. 2010, 10: 840-848. 10.2174/156800910793357970.
Hahn O, Stadler W: Sorafenib. Curr Opin Oncol. 2006, 18: 615-621. 10.1097/01.cco.0000245316.82391.52.
Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA: BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004, 64: 7099-7109. 10.1158/0008-5472.CAN-04-1443.
Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Koch A, Evers BM: PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Res. 2010, 30: 4951-4958.
Lu X, Tang X, Guo W, Ren T, Zhao H: Sorafenib induces growth inhibition and apoptosis of human chondrosarcoma cells by blocking the RAF/ERK/MEK pathway. J Surg Oncol. 2010, 102: 821-826. 10.1002/jso.21661.
Hasskarl J: Sorafenib. Recent Results Cancer Res. 2010, 184: 61-70. 10.1007/978-3-642-01222-8_5.
Siegelin MD, Raskett CM, Gilbert CA, Ross AH, Altieri DC: Sorafenib exerts anti-glioma activityin vitroandin vivo. Neurosci Lett. 2010, 478: 165-170. 10.1016/j.neulet.2010.05.009.
Jane EP, Premkumar DR, Pollack IF: Coadministration of sorafenib with rottlerin potently inhibits cell proliferation and migration in human malignant glioma cells. J Pharmacol Exp Ther. 2006, 319: 1070-1080. 10.1124/jpet.106.108621.
Nabors LB, Supko JG, Rosenfeld M, Chamberlain M, Phuphanich S, Batchelor T, Desideri S, Ye X, Wright J, Gujar S, Grossman SA, New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium: Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma. Neuro Oncol. 2011, 13: 1324-1330. 10.1093/neuonc/nor145.
Krueger T, Westenfeld R, Schurgers L, Brandenburg V: Coagulation meets calcification: the vitamin K system. Int J Artif Organs. 2009, 32: 67-74.
Okayasu H, Ishihara M, Satoh K, Sakagami H: Cytotoxic activity of vitamins K1, K2 and K3 against human oral tumor cell lines. Anticancer Res. 2001, 21: 2387-2392.
Showalter SL, Wang Z, Costantino CL, Witkiewicz AK, Yeo CJ, Brody JR, Carr BI: Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway. J Gastroenterol Hepatol. 2010, 25: 738-744. 10.1111/j.1440-1746.2009.06085.x.
Carr BI, Wang Z, Wang M, Cavallini A, D’Alessandro R, Refolo MG: c-Met-Akt pathway-mediated enhancement of inhibitory c-Raf phosphorylation is involved in vitamin K1 and sorafenib synergy on HCC growth inhibition. Cancer Biol Ther. 2011, 12: 531-538. 10.4161/cbt.12.6.16053.
Huang CS, Lyu SC, Hu ML: Synergistic effects of the combination of beta-ionone and sorafenib on metastasisof human hepatoma SK-Hep-1 cells. Invest New Drugs. in press
Roy CS, Karmakar S, Banik NL, Ray SK: Synergistic efficacy of sorafenib and genistein in growth inhibition by downregulating angiogenic and survival factors and increasing apoptosis throughupregulation of p53 and p21 in malignant neuroblastoma cells having N-Mycamplification or non-amplification. Invest New Drugs. 2010, 28: 812-824. 10.1007/s10637-009-9324-7.
Yip KW, Reed JC: Bcl-2 family proteins and cancer. Oncogene. 2008, 27: 6398-6406. 10.1038/onc.2008.307.
Fulda S, Galluzzi L, Kroemer G: Targeting mitochondria for cancer therapy. Nat Rev Drug Discov. 2010, 9: 447-464. 10.1038/nrd3137.
Heath-Engel HM, Chang NC, Shore GC: The endoplasmic reticulum in apoptosis and autophagy: role of the BCL-2 protein family. Oncogene. 2008, 27: 6419-6433. 10.1038/onc.2008.309.
Akgul C: Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci. 2009, 66: 1326-1336. 10.1007/s00018-008-8637-6.
Yu C, Bruzek LM, Meng XW, Gores GJ, Carter CA, Kaufmann SH, Adjei AA: The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43–9006. Oncogene. 2005, 24: 6861-6869. 10.1038/sj.onc.1208841.
Domina AM, Vrana JA, Gregory MA, Hann SR, Craig RW: MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene. 2004, 23: 5301-5315. 10.1038/sj.onc.1207692.