Faculty Collaboration Database

Circumvention of confluence-dependent resistance in a human multi-drug-resistant colon-cancer cell line. Int J Cancer 1995 Jun 09;61(6):873-9

Date

06/09/1995

Pubmed ID

7790124

DOI

10.1002/ijc.2910610621

Scopus ID

2-s2.0-0029057912 (requires institutional sign-in at Scopus site)   24 Citations

Abstract

Colorectal adenocarcinomas are inherently resistant to anthracyclines and other topoisomerase-II inhibitors. Resistance to doxorubicin of colon cancer cells (Caco2) depends on 2 main mechanisms. The first is typical multi-drug resistance, characterized by the mdr1 gene and its product the P170 membrane glycoprotein. P170 effluxes anthracyclines out of cancer cells and is antagonized in vitro by verapamil. The second mechanism, which develops when cell-culture density increases, we have designated confluence-dependent resistance. Confluence-dependent resistance depends on the reduced topoisomerase II content of the G0/G1-phase cells which accumulate in the confluent population. We show here that short treatments of confluent Caco2 cells with slightly toxic concentrations of DNA-damaging agents (cisplatin, melphalan or mitomycin C) produced a transient accumulation of cells in S- and G2/M-phases of the cell cycle. Concomitantly with the increase in the S-phase population, the topoisomerase II cellular level and the sensitivity of cells to doxorubicin were greatly enhanced. Overcoming confluence-dependent resistance through S-phase accumulation and inhibition of multi-drug resistance by verapamil were fully additive, and a nearly complete reversal of confluent Caco2 cells' resistance to doxorubicin was obtained when both strategies were combined.

Author List

Garrido C, Chauffert B, Pinard D, Tibaut F, Genne P, Assem M, Dimanche-Boitrel MT

Author

Mahfoud Assem PharmD Associate Professor in the School of Pharmacy Administration department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Antineoplastic Agents
Cell Cycle
Cisplatin
Colonic Neoplasms
DNA Topoisomerases, Type II
Doxorubicin
Drug Resistance, Multiple
Drug Screening Assays, Antitumor
Humans
Melphalan
Mitomycins
Topoisomerase II Inhibitors
Tumor Cells, Cultured