Conditioned media from human macrophages of M1 phenotype attenuate the cytotoxic effect of 5-fluorouracil on the HT-29 colon cancer cell line
| العنوان: | Conditioned media from human macrophages of M1 phenotype attenuate the cytotoxic effect of 5-fluorouracil on the HT-29 colon cancer cell line |
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| المؤلفون: | Hedbrant, Alexander, Erlandsson, Ann, Delbro, Dick, 1950, Wijkander, Jonny |
| المصدر: | International Journal of Oncology. 46(1):37-46 |
| مصطلحات موضوعية: | Chemotherapy, 5-fluorouracil, colon cancer cell line, HT-29, CACO-2, M1 macrophages, M2 macrophages, cell cycle, Onkologi, Oncology |
| الوصف: | Resistance of tumor cells to chemotherapy, such as 5-fluorouracil (5-FU), is an obstacle for successful treatment of cancer. As a follow-up of a previous study we have investigated the effect of conditioned media (CM) from macrophages of M1 or M2 phenotypes on 5-FU cytotoxicity on the colon cancer cell lines HT-29 and CACO-2. HT-29 cells, but not CACO-2 cells, having been treated with a combination of M1 CM and 5-FU recovered their cell growth to a much larger extent compared to cells having been treated with 5-FU alone when further cultured for 7 days in fresh media. M1 CM treatment of HT-29, but not CACO-2 cells, induced cell cycle arrest in the G(0)/G(1) and G(2)/M phases. 5-FU treatment induced accumulation of cells in S-phase in both HT-29 and CACO-2 cells. This accumulation of cells in S-phase was attenuated by combined M1 CM and 5-FU treatment in HT-29 cells, but not in CACO-2 cells. The mRNA expression of cell cycle regulatory proteins and 5-FU metabolic enzymes were analyzed in an attempt to find possible mechanisms for the M1 CM induced attenuation of 5-FU cytotoxicity in HT-29. Thymidylate synthetase (TS) and thymidine phosphorylase (TP) were found to be substantially downregulated and upregulated, respectively, in HT-29 cells treated with M1 CM, making them unlikely as mediators of reduced 5-FU cytotoxicity. Among cell cycle regulating proteins, p21 was induced in HT-29 cells, but not in CACO-2 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 HT-29 and neither did it change the growth recovery after combined treatment of HT-29 cells with M1 CM and 5-FU. In conclusion, treatment of HT-29 cells with M1 CM reduces the cytotoxic effect of 5-FU and this is mediated by a M1 CM induced cell cycle arrest in the G(0)/G(1) and G(2)/M phases. So far, we lack an explanation why this action is absent in the CACO-2 cells. The current findings may be important for optimization of chemotherapy in colon cancer. |
| وصف الملف: | |
| URL الوصول: | https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-40154 https://doi.org/10.3892/ijo.2014.2696 |
| قاعدة البيانات: | SwePub |
| تدمد: | 10196439 17912423 |
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| DOI: | 10.3892/ijo.2014.2696 |