title: Differential inhibitory effects of two Raf-targeting drugs, sorafenib and PLX4720, on the growth of multidrug-resistant cells.
abstract: B-Raf is the most frequently mutated protein kinase in the MAPK signaling cascade in human cancers, making it an important therapeutic target. Here, we describe the differential effects of two Raf-targeting drugs, sorafenib and PLX4720, on multidrug-resistant v-Ha-ras-transformed cells (Ras-NIH 3T3/Mdr). We demonstrate that the growth of the NIH 3T3/Mdr cell line was affected in a dose-dependent manner more significantly by the pan-Raf inhibitor sorafenib than by the selective mutant B-Raf inhibitor PLX4720. Despite their differential effects on LKB1/AMPK phosphorylation, both sorafenib and PLX4720 inhibited downstream mTOR signaling with concomitant induction of autophagy, implying that the differential effects of sorafenib and PLX4720 on multidrug-resistant cells might not be due to different levels of autophagy and apoptosis. Interestingly, sorafenib caused a dose-dependent increase in rhodamine 123 uptake and retention. More importantly, sorafenib reversed the resistance to paclitaxel in Ras-NIH 3T3/Mdr cells. Moreover, MEK/ERK signaling was hyperactivated by the selective mutant B-Raf inhibitor PLX4720 and inhibited by the pan-Raf inhibitor sorafenib. Our data suggest that sorafenib sensitivity in MDR cells is mediated through the inhibition of P-glycoprotein activity following strong inhibition of Raf/MEK/ERK signaling. Thus, Raf inhibition with sorafenib might be a promising approach to abrogate the multidrug resistance of cancer cells.
authors.affiliation: Division of Life Sciences, College of Life Sciences and Bioengineering, University of Incheon, 12-1 Songdo-dong, Yeonsu-gu, Incheon 406-772, Republic of Korea.
authors.forename: Ki-Hwan
authors.initials: KH
authors.lastname: Eum
authors.forename: Soon Kil
authors.initials: SK
authors.lastname: Ahn
authors.forename: Hara
authors.initials: H
authors.lastname: Kang
authors.forename: Michael
authors.initials: M
authors.lastname: Lee
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000077157:Sorafenib; D013449:Sulfonamides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007211:Indoles; C528407:PLX 4720; D010671:Phenylurea Compounds; D013449:Sulfonamides; D009536:Niacinamide; D000077157:Sorafenib; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3