Restriction of cisplatin induction of acute apoptosis to a subpopulation of cells in a three-dimensional carcinoma culture model.

Full Abstract

Cisplatin is a clinically important chemotherapeutical agent used to treat epithelial malignancies. High concentrations (20-100 microM) of cisplatin have been used in numerous studies to induce apoptosis of carcinoma cells grown in monolayer culture over 24-48 hr. These conditions may not be relevant to 3-D tumor tissue in vivo and the importance of apoptosis for tumor response is controversial. We here studied the effects of cisplatin on a 3-D colon carcinoma in vitro model (multicellular spheroids). Cisplatin at a dose of 40 microM induced active caspase-3 preferentially in the peripheral 30 microm cell layer of spheroids, mainly during late stages (72-96 hr). The p53 response to cisplatin was also largely confined to peripheral cell layers. Despite the use of a high cisplatin concentration, a significant fraction of the cells in the spheroids survived treatment. A high proportion of surviving cells stained positive for beta-galactosidase, a marker of premature senescence. Cells growth-arrested by cisplatin treatment showed a higher spontaneous cell death rate than untreated proliferating cells. We propose that acute apoptosis is of minor significance for the overall response of carcinoma cells to cisplatin treatment.

Author information

Author/s: Fayad, Walid (W); Brnjic, Slavica (S); Berglind, Daniel (D); Blixt, Susanna (S); Shoshan, Maria C (MC); Berndtsson, Maria (M); Olofsson, Maria Hägg (MH); Linder, Stig (S);

Affiliation: Department of Oncology and Pathology, Karolinska Institute and Hospital, Cancer Center Karolinska, Stockholm, Sweden.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: International journal of cancer. Journal international du cancer (Int J Cancer), published in United States. (Language: eng)

Reference: 2009-Nov; vol 125 (issue 10) : pp 2450-5

Dates: Created 2009/09/28; Completed 2009/11/05;

PMID: 19670329, status: MEDLINE (last retrieval date: 11/5/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Cell Culture Techniques
Cell Cycle
Cell Cycle Proteins - metabolism
Cell Line, Tumor
Cell Proliferation - drug effects
Cisplatin - pharmacology

Colonic Neoplasms - drug therapy; pathology
DNA Damage - drug effects
Humans
Immunoenzyme Techniques
Mice
Mice, SCID
Spheroids, Cellular
Tumor Suppressor Protein p53 - metabolism
Xenograft Model Antitumor Assays

Associated Chemicals: Antineoplastic Agents (0) ; Cell Cycle Proteins (0) ; Tumor Suppressor Protein p53 (0) ; Cisplatin (15663-27-1)

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