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Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment.

ABSTRACT: In the present study, we evaluated the antitumor effect of two synthetic analogs of vitamin D, namely PRI-2191 [(24R)-1,24-dihydroxyvitamin D3] and PRI-2205 (5,6-trans calcipotriol), in combined human colon HT-29 cancer treatment with 5-fluorouracil (5-FU). Mice bearing HT-29 tumors transplanted subcutaneously or orthotopically were injected with vitamin D analogs and 5-FU in various schedules. A statistically significant inhibition of subcutaneous or orthotopic tumor growth was observed as a result of combined therapy. In HT-29 tumors and in cells from in vitro culture, we observed increased vitamin D receptor (VDR) expression after treatment with either PRI-2205 or 5-FU alone, or in combination. Moreover, PRI-2205 decreased the percentage of cells from intestinal tumors in G2/M and S stages and increased sub-G1. Increased VDR expression was also observed after combined treatment of mice with 5-FU and PRI-2191. Moreover, our docking studies showed that PRI-2205 has stronger affinity for VDR, DBP and CAR/RXR ligand binding domains than PRI-2191. PRI-2191 analog, used with 5-FU, increased the percentage of subcutaneous tumor cells in G0/G1 and decreased the percentage in G2/M, S and sub-G1 populations as compared to 5-FU alone. In in vitro studies, we observed increased expression of p21 and p-ERK1/2 diminution via use of both analogs as compared to use of 5-FU alone. Simultaneously, PRI-2191 antagonizes some pro-apoptotic activities of 5-FU in vitro. However, in spite of these disadvantageous effects in terms of apoptosis, the therapeutic effect expressed as tumor growth retardation by PRI-2191 is significant. Our results suggest that the mechanism of potentiation of 5-FU antitumor action by both analogs is realized via increased p21 expression and decreased p-ERK1/2 level which may lead to diminution of thymidylate synthase expression. Higher binding affinity for VDR, DBP, but also for CAR\RXR ligand binding domain of PRI-2205 may, in part, explain its very low toxicity with sustained anticancer activity.

SUBMITTER: Milczarek M

PROVIDER: S-EPMC4091879 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment.

Milczarek Magdalena M Filip-Psurska Beata B Swiętnicki Wiesław W Kutner Andrzej A Wietrzyk Joanna J

Oncology reports 20140611 2

In the present study, we evaluated the antitumor effect of two synthetic analogs of vitamin D, namely PRI-2191 [(24R)-1,24-dihydroxyvitamin D3] and PRI-2205 (5,6-trans calcipotriol), in combined human colon HT-29 cancer treatment with 5-fluorouracil (5-FU). Mice bearing HT-29 tumors transplanted subcutaneously or orthotopically were injected with vitamin D analogs and 5-FU in various schedules. A statistically significant inhibition of subcutaneous or orthotopic tumor growth was observed as a re ...[more]

PMID: 24919507

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Project description: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 G0/G1 and G2/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 G0/G1 and G2/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.

Dataset Information

Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment.

Publications

Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment.

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