Increased MDR1 expression in normal and malignant peripheral blood mononuclear cells obtained from patients receiving depsipeptide (FR901228, FK228, NSC630176).
The increased expression of markers associated with a differentiated phenotype, such as P-glycoprotein (Pgp), follows treatment with histone deacetylase inhibitors. Because depsipeptide (FR901228, FK228, NSC630176) is a substrate for Pgp, up-regulation of the gene that encodes it, MDR1, would mean that depsipeptide induces its own mechanism of resistance. To examine the effect of depsipeptide on expression of ATP-binding cassette transporters associated with multidrug resistance, the kidney cancer cell lines 108, 121, 127, and 143 were treated with depsipeptide and evaluated by quantitative reverse transcription-PCR. Increased levels of MDR1 (1.3- to 6.3-fold) and ABCG2 (3.2- to 11.1-fold) but not MRP1 (0.9- to 1.3-fold) were observed. The induced Pgp transported the fluorescent substrates rhodamine 123, bisantrene, calcein-AM, BODIPY-vinblastine, and BODIPY-paclitaxel. In normal peripheral blood mononuclear cells (PBMC) and circulating tumor cells obtained from patients receiving depsipeptide, increased levels of histone H3 acetylation were found. We next examined MDR1 levels in normal and malignant PBMCs obtained from 15 patients enrolled in clinical trials with depsipeptide and detected up to a 6-fold increase in normal PBMCs and up to an 8-fold increase in circulating tumor cells after depsipeptide administration. In one patient with Sézary syndrome, increased MDR1 gene expression was accompanied by increased cell surface Pgp expression in circulating Sézary cells as determined by measurement of MRK-16 staining by flow cytometry. These studies suggest that depsipeptide induces its own mechanism of resistance and thus provide a basis for clinical trials evaluating depsipeptide in combination with a Pgp inhibitor.
Cancer Therapeutics Branch, Center for Cancer Research, NIH, National Cancer Institute, Bethesda, Maryland 20892, USA. robeyr@mail.nih.gov
Robert W
RW
Robey
Zhirong
Z
Zhan
Richard L
RL
Piekarz
Ganesh L
GL
Kayastha
Tito
T
Fojo
Susan E
SE
Bates
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000107:Acetylation; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D016049:Didanosine / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D051597:Hippocalcin / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009360:Neoplastic Cells, Circulating / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012751:Sezary Syndrome / Q000188:drug therapy / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D000963:Antimetabolites; D000970:Antineoplastic Agents; D047630:Depsipeptides; D016049:Didanosine; D004317:Doxorubicin; D051597:Hippocalcin; D006657:Histones; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017239:Paclitaxel; D012333:RNA, Messenger; C116614:ABCG2 protein, human; C087123:romidepsin; C421109:multidrug resistance-associated protein 1