Multidrug Resistance in Androgen-independent Growing Rat Prostate Carcinoma Cells is Mediated by P-glycoprotein

Overview

Journal Urol Res

Specialty Urology

Date 1997 Jan 1

PMID 9079744

Citations 3

Authors

M J Siegsmund

C Kreukler

A Steidler

T Nebe

K U Kohrmann

P Alken

Affiliations

Soon will be listed here.

Abstract

Prostate carcinomas are in general resistant against virtually all cytotoxic drugs. Up to now it has not been thoroughly evaluated whether specific resistance factors, such as the expression of the MDR1 gene, play a role in this multi-agent resistance and whether there is a link between drug resistance and hormone-independent growth. We investigated the resistance patterns of a hormone-sensitive and four hormone-independent Dunning rat carcinoma sublines against four drugs which are substrates of P-glycoprotein (vinblastine, taxol, doxorubicin, and etoposide) and two agents (methotrexate and cis-platinum) which are not transported by this efflux pump. All hormone-insensitive sublines, AT.1, AT. 3.1., MatLu and Mat LyLu, continuously showed a clearly enhanced resistance (3- to 26-fold) against the P-glycoprotein substrates, compared to the hormone-sensitive subline G. Only two of the androgen-independent sublines displayed enhanced resistance against methotrexate, whereas all of them were more sensitive against cisplatin than the androgen-sensitive G cells. By addition of verapamil the resistance against vinblastine (9- to 10-fold) and taxol (6.7- to 26.7-fold) in the hormone-insensitive cells could be almost totally reversed. Furthermore, the fluorescent P-glycoprotein substrate rhodamine-123 was effectively pumped out of the four tested hormone-independent cell lines, whereas the hormone-sensitive G cells were unable to extrude the dye. By reverse transcriptase polymerase chain reaction (RT-PCR) with primers specific for the rat mdr1b gene, the homologue to the human MDR1 gene, we could easily detect mdr1b expression in the androgen independent cell lines, but not in the G cells. Our results suggest that the product of the rat mdr1b gene is involved in the multidrug resistance of androgen-independent Dunning prostate carcinoma cells.

Citing Articles

Priming cancer cells for drug resistance: role of the fibroblast niche.

Fang W, Yao M, Cheng N Front Biol (Beijing). 2014; 9(2):114-126.

PMID: 25045348 PMC: 4101896. DOI: 10.1007/s11515-014-1300-8.

Metastasizing, Luciferase Transduced MAT‑Lu Rat Prostate Cancer Models: Follow up of Bolus and Metronomic Therapy with Doxorubicin as Model Drug.

Jantscheff P, Esser N, Geipel A, Woias P, Ziroli V, Goldschmidtboing F Cancers (Basel). 2013; 3(2):2679-95.

PMID: 24212827 PMC: 3757437. DOI: 10.3390/cancers3022679.

Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs.

Thews O, Gassner B, Kelleher D, Schwerdt G, Gekle M Neoplasia. 2006; 8(2):143-52.

PMID: 16611407 PMC: 1578510. DOI: 10.1593/neo.05697.

References

Bhushan A, Abramson R, Chiu J, Tritton T . Expression of c-fos in human and murine multidrug-resistant cells. Mol Pharmacol. 1992; 42(1):69-74. View

Holzmayer T, Hilsenbeck S, Von Hoff D, Roninson I . Clinical correlates of MDR1 (P-glycoprotein) gene expression in ovarian and small-cell lung carcinomas. J Natl Cancer Inst. 1992; 84(19):1486-91. DOI: 10.1093/jnci/84.19.1486. View

Mickisch G, Merlino G, Galski H, Gottesman M, Pastan I . Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance. Proc Natl Acad Sci U S A. 1991; 88(2):547-51. PMC: 50848. DOI: 10.1073/pnas.88.2.547. View

van der Valk P, van Kalken C, Ketelaars H, Broxterman H, Scheffer G, Kuiper C . Distribution of multi-drug resistance-associated P-glycoprotein in normal and neoplastic human tissues. Analysis with 3 monoclonal antibodies recognizing different epitopes of the P-glycoprotein molecule. Ann Oncol. 1990; 1(1):56-64. View

van der Kwast T, Schalken J, Ruizeveld de Winter J, van Vroonhoven C, Mulder E, Boersma W . Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int J Cancer. 1991; 48(2):189-93. DOI: 10.1002/ijc.2910480206. View

Hsu S, Cohen D, Kirschner L, Lothstein L, Hartstein M, Horwitz S . Structural analysis of the mouse mdr1a (P-glycoprotein) promoter reveals the basis for differential transcript heterogeneity in multidrug-resistant J774.2 cells. Mol Cell Biol. 1990; 10(7):3596-606. PMC: 360796. DOI: 10.1128/mcb.10.7.3596-3606.1990. View

Doroshow J, Akman S, Esworthy S, Chu F, Burke T . Doxorubicin resistance conferred by selective enhancement of intracellular glutathione peroxidase or superoxide dismutase content in human MCF-7 breast cancer cells. Free Radic Res Commun. 1991; 12-13 Pt 2:779-81. DOI: 10.3109/10715769109145859. View

Huff A, Ward 4th R, Kreuzer K . Mutational alteration of the breakage/resealing subunit of bacteriophage T4 DNA topoisomerase confers resistance to antitumor agent m-AMSA. Mol Gen Genet. 1990; 221(1):27-32. DOI: 10.1007/BF00280363. View

Akman S, Forrest G, Chu F, Esworthy R, Doroshow J . Antioxidant and xenobiotic-metabolizing enzyme gene expression in doxorubicin-resistant MCF-7 breast cancer cells. Cancer Res. 1990; 50(5):1397-402. View

10.

Fojo A, Ueda K, Slamon D, Poplack D, Gottesman M, Pastan I . Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A. 1987; 84(1):265-9. PMC: 304184. DOI: 10.1073/pnas.84.1.265. View

11.

Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987; 162(1):156-9. DOI: 10.1006/abio.1987.9999. View

12.

Goldstein L, Galski H, Fojo A, Willingham M, Lai S, Gazdar A . Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst. 1989; 81(2):116-24. DOI: 10.1093/jnci/81.2.116. View

13.

Cole S, Downes H, Slovak M . Effect of calcium antagonists on the chemosensitivity of two multidrug-resistant human tumour cell lines which do not overexpress P-glycoprotein. Br J Cancer. 1989; 59(1):42-6. PMC: 2246955. DOI: 10.1038/bjc.1989.9. View

14.

Twentyman P . Modification of cytotoxic drug resistance by non-immuno-suppressive cyclosporins. Br J Cancer. 1988; 57(3):254-8. PMC: 2246508. DOI: 10.1038/bjc.1988.55. View

15.

Shinoda H, Inaba M, Tsuruo T . In vivo circumvention of vincristine resistance in mice with P388 leukemia using a novel compound, AHC-52. Cancer Res. 1989; 49(7):1722-6. View

16.

Chiu R, Boyle W, Meek J, Smeal T, Hunter T, Karin M . The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell. 1988; 54(4):541-52. DOI: 10.1016/0092-8674(88)90076-1. View

17.

Buttyan R, Zakeri Z, Lockshin R, Wolgemuth D . Cascade induction of c-fos, c-myc, and heat shock 70K transcripts during regression of the rat ventral prostate gland. Mol Endocrinol. 1988; 2(7):650-7. DOI: 10.1210/mend-2-7-650. View

18.

Kelley S, Basu A, Teicher B, Hacker M, Hamer D, Lazo J . Overexpression of metallothionein confers resistance to anticancer drugs. Science. 1988; 241(4874):1813-5. DOI: 10.1126/science.3175622. View

19.

Leger J, Montpetit M, Tenniswood M . Characterization and cloning of androgen-repressed mRNAs from rat ventral prostate. Biochem Biophys Res Commun. 1987; 147(1):196-203. DOI: 10.1016/s0006-291x(87)80106-7. View

20.

Nooter K, Oostrum R, Deurloo J . Effects of verapamil on the pharmacokinetics of daunomycin in the rat. Cancer Chemother Pharmacol. 1987; 20(2):176-8. DOI: 10.1007/BF00253975. View