Conditioned media from human macrophages of M1 phenotype attenuate the cytotoxic effect of 5fluorouracil on the HT29 colon cancer cell line.
Int J Oncol
; 46(1): 37-46, 2015 Jan.
Article
in En
| MEDLINE
| ID: mdl-25310018
ABSTRACT
Resistance of tumor cells to chemotherapy, such as 5fluorouracil (5FU), is an obstacle for successful treatment of cancer. As a followup of a previous study we have investigated the effect of conditioned media (CM) from macrophages of M1 or M2 phenotypes on 5FU cytotoxicity on the colon cancer cell lines HT29 and CACO2. HT29 cells, but not CACO2 cells, having been treated with a combination of M1 CM and 5FU recovered their cell growth to a much larger extent compared to cells having been treated with 5FU alone when further cultured for 7 days in fresh media. M1 CM treatment of HT29, but not CACO2 cells, induced cell cycle arrest in the G0/G1 and G2/M phases. 5FU treatment induced accumulation of cells in Sphase in both HT29 and CACO2 cells. This accumulation of cells in Sphase was attenuated by combined M1 CM and 5FU treatment in HT29 cells, but not in CACO2 cells. The mRNA expression of cell cycle regulatory proteins and 5FU metabolic enzymes were analyzed in an attempt to find possible mechanisms for the M1 CM induced attenuation of 5FU cytotoxicity in HT29. Thymidylate synthetase (TS) and thymidine phosphorylase (TP) were found to be substantially downregulated and upregulated, respectively, in HT29 cells treated with M1 CM, making them unlikely as mediators of reduced 5FU cytotoxicity. Among cell cycle regulating proteins, p21 was induced in HT29 cells, but not in CACO2 cells, in response to M1 CM treatment. However, small interfering RNA (siRNA) knockdown of p21 had no effect on the M1 CM induced cell cycle arrest seen in HT29 and neither did it change the growth recovery after combined treatment of HT29 cells with M1 CM and 5FU. In conclusion, treatment of HT29 cells with M1 CM reduces the cytotoxic effect of 5FU and this is mediated by a M1 CM induced cell cycle arrest in the G0/G1 and G2/M phases. So far, we lack an explanation why this action is absent in the CACO2 cells. The current findings may be important for optimization of chemotherapy in colon cancer.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Culture Media, Conditioned
/
Colonic Neoplasms
/
Drug Resistance, Neoplasm
/
Fluorouracil
/
Macrophages
/
Antimetabolites, Antineoplastic
Limits:
Humans
Language:
En
Journal:
Int J Oncol
Journal subject:
NEOPLASIAS
Year:
2015
Document type:
Article
Affiliation country:
Sweden