Targeting mammalian target of rapamycin to both downregulate and disable the P-glycoprotein pump in multidrug-resistant B-cell lymphoma cell lines.
Previous studies have shown that rapamycin can inhibit the growth of several different types of human tumor cells in vitro. In certain cases, it can reverse the phenotype of multidrug resistant (MDR) cells. However, there is limited information concerning its effect on P-glycoprotein (P-gp), a pump that is responsible for chemoresistance in many MDR cells. We investigated the effect of rapamycin on both P-gp function and the MDR phenotype in four cell lines. One cell line was also xenografted into SCID mice to determine whether rapamycin would chemosensitize the cells in vivo. Because rapamycin targets the mammalian target of rapamycin (mTOR) pathway, we also used our cells to confirm that rapamycin modified the expression of mTOR and effectively suppressed the phosphorylation of two downstream effector molecules in the mTOR pathway, S6K1, and 4E-BP1. We demonstrated that it inhibited the growth of the three cell lines in vitro and one in vivo showing that it modulated both the expression and function of P-gp and chemosensitized the three cell lines as effectively as verapamil.
Pop
Iliodora V
IV
Cancer Immunobiology Center, UT Southwestern Medical Center, Dallas, Texas 75390-8576, USA.
Pop
Laurentiu M
LM
Ghetie
Maria-Ana
MA
Vitetta
Ellen S
ES
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D011494:Protein Kinases / Q000096:biosynthesis*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus