Screening of an annotated compound library for drug activity in a resistant myeloma cell line.
OBJECTIVE
Resistance to anticancer drugs is a major problem in chemotherapy. In order to identify drugs with selective cytotoxic activity in drug-resistant cancer cells, the annotated compound library LOPAC1280, containing compounds from 56 pharmacological classes, was screened in the myeloma cell line RPMI 8226 and its doxorubicin-resistant subline 8226/Dox40.


METHODS
Cell survival was measured by the Fluorometric Microculture Cytotoxicity Assay.


RESULTS
Selective cytotoxic activity in 8226/Dox40 was obtained for 33 compounds, with the most pronounced difference observed for the glucocorticoids. A microarray analysis of the cells showed a difference in mRNA-expression for the glucocorticoid receptor suggesting potential mechanisms for the difference in glucocorticoid sensitivity. In the presence of the glucocorticoid-receptor antagonist RU486, the sensitivity to the glucocorticoids was reduced and a similar effect level in RPMI 8226 and 8226/Dox40 was achieved.


CONCLUSIONS
In conclusion, screening of mechanistically annotated compounds on drug-resistant cancer cells can identify compounds with selective activity and provide a basis for the development of novel treatments of drug-resistant malignancies.
Rickardson
Linda
L
Department of Medical Sciences, Division of Clinical Pharmacology, Uppsala University, 751 85, Uppsala, Sweden. Linda.Rickardson@medsci.uu.se
Fryknäs
Mårten
M
Haglund
Caroline
C
Lövborg
Henrik
H
Nygren
Peter
P
Gustafsson
Mats G
MG
Isaksson
Anders
A
Larsson
Rolf
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001623:Betamethasone / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015735:Mifepristone / Q000494:pharmacology; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D000970:Antineoplastic Agents; D005938:Glucocorticoids; C497713:NR3C1 protein, human; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D004317:Doxorubicin; D001623:Betamethasone