Open Access

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

  • Authors:
    • Magdalena Milczarek
    • Beata Filip-Psurska
    • Wiesław Świętnicki
    • Andrzej Kutner
    • Joanna Wietrzyk
  • View Affiliations

  • Published online on: June 11, 2014     https://doi.org/10.3892/or.2014.3247
  • Pages: 491-504
  • Copyright: © Milczarek et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.
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August-2014
Volume 32 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Milczarek M, Filip-Psurska B, Świętnicki W, Kutner A and Wietrzyk J: Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment. Oncol Rep 32: 491-504, 2014.
APA
Milczarek, M., Filip-Psurska, B., Świętnicki, W., Kutner, A., & Wietrzyk, J. (2014). Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment. Oncology Reports, 32, 491-504. https://doi.org/10.3892/or.2014.3247
MLA
Milczarek, M., Filip-Psurska, B., Świętnicki, W., Kutner, A., Wietrzyk, J."Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment". Oncology Reports 32.2 (2014): 491-504.
Chicago
Milczarek, M., Filip-Psurska, B., Świętnicki, W., Kutner, A., Wietrzyk, J."Vitamin D analogs combined with 5-fluorouracil in human HT-29 colon cancer treatment". Oncology Reports 32, no. 2 (2014): 491-504. https://doi.org/10.3892/or.2014.3247