Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia

Hagar Sharabani, Evgeny Izumchenko, Qing Wang, Rita Kreinin, Michael Steiner, Zeev Barvish, Michael Kafka, Yoav Sharoni, Joseph Levy, Milan Uskokovic, George P. Studzinski, Michael Danilenko

Research output: Contribution to journalArticle

Abstract

1α,25-dihydroxyvitamin D3 (1,25D3) is a powerful differentiation agent, which has potential for treatment of myeloid leukemias and other types of cancer, but the calcemia produced by pharmacologically active doses precludes the use of this agent in the clinic. We have shown that carnosic acid, the major rosemary polyphenol, enhances the differentiating and antiproliferative effects of low concentrations of 1,25D3 in human myeloid leukemia cell lines (HL60, U937). Here we translated these findings to in vivo conditions using a syngeneic mouse leukemia tumor model. To this end, we first demonstrated that as in HL60 cells, differentiation of WEHI-3B D- murine myelomonocytic leukemia cells induced by 1 nM 1,25D3 or its low-calcemic analog, 1,25-dihydroxy-16-ene-5,6-trans-cholecalciferol (Ro25-4020), can be synergistically potentiated by carnosic acid (10 μM) or the carnosic acid-rich ethanolic extract of rosemary leaves. This effect was accompanied by cell cycle arrest in G0+G1 phase and a marked inhibition of cell growth. In the in vivo studies, i.p._injections of 2 μg Ro25-4020 in Balb/c mice bearing WEHI-3B D- tumors produced a significant delay in tumor appearance and reduction in tumor size, without significant toxicity. Another analog, 1,25-dihydroxy-16,23Z-diene-20-epi-26,27-hexafluoro-19-nor-cholecalciferol (Ro26-3884) administered at the same dose was less effective than Ro25-4020 and profoundly toxic. Importantly, combined treatment with 1% dry rosemary extract (mixed with food) and 1 μg Ro25-4020 resulted in a strong cooperative antitumor effect, without inducing hypercalcemia. These results indicate for the first time that a plant polyphenolic preparation and a vitamin D derivative can cooperate not only in inducing leukemia cell differentiation in vitro, but also in the antileukemic activity in vivo. These data may suggest novel protocols for chemoprevention or differentiation therapy of myeloid leukemia.

Original languageEnglish (US)
Pages (from-to)3012-3021
Number of pages10
JournalInternational Journal of Cancer
Volume118
Issue number12
DOIs
StatePublished - Jun 15 2006
Externally publishedYes

Fingerprint

Myeloid Leukemia
Cholecalciferol
Calcitriol
Leukemia
Hypercalcemia
Neoplasms
Cell Differentiation
Plant Preparations
Cell Cycle Resting Phase
Poisons
HL-60 Cells
Chemoprevention
G1 Phase
Polyphenols
Myeloid Cells
Cell Cycle Checkpoints
Vitamin D
Therapeutics
Cell Line
Food

Keywords

  • Carnosic acid
  • Cell cycle
  • Differentiation
  • Myeloid leukemia
  • Vitamin D

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Sharabani, H., Izumchenko, E., Wang, Q., Kreinin, R., Steiner, M., Barvish, Z., ... Danilenko, M. (2006). Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia. International Journal of Cancer, 118(12), 3012-3021. https://doi.org/10.1002/ijc.21736

Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia. / Sharabani, Hagar; Izumchenko, Evgeny; Wang, Qing; Kreinin, Rita; Steiner, Michael; Barvish, Zeev; Kafka, Michael; Sharoni, Yoav; Levy, Joseph; Uskokovic, Milan; Studzinski, George P.; Danilenko, Michael.

In: International Journal of Cancer, Vol. 118, No. 12, 15.06.2006, p. 3012-3021.

Research output: Contribution to journalArticle

Sharabani, H, Izumchenko, E, Wang, Q, Kreinin, R, Steiner, M, Barvish, Z, Kafka, M, Sharoni, Y, Levy, J, Uskokovic, M, Studzinski, GP & Danilenko, M 2006, 'Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia', International Journal of Cancer, vol. 118, no. 12, pp. 3012-3021. https://doi.org/10.1002/ijc.21736
Sharabani, Hagar ; Izumchenko, Evgeny ; Wang, Qing ; Kreinin, Rita ; Steiner, Michael ; Barvish, Zeev ; Kafka, Michael ; Sharoni, Yoav ; Levy, Joseph ; Uskokovic, Milan ; Studzinski, George P. ; Danilenko, Michael. / Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia. In: International Journal of Cancer. 2006 ; Vol. 118, No. 12. pp. 3012-3021.
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abstract = "1α,25-dihydroxyvitamin D3 (1,25D3) is a powerful differentiation agent, which has potential for treatment of myeloid leukemias and other types of cancer, but the calcemia produced by pharmacologically active doses precludes the use of this agent in the clinic. We have shown that carnosic acid, the major rosemary polyphenol, enhances the differentiating and antiproliferative effects of low concentrations of 1,25D3 in human myeloid leukemia cell lines (HL60, U937). Here we translated these findings to in vivo conditions using a syngeneic mouse leukemia tumor model. To this end, we first demonstrated that as in HL60 cells, differentiation of WEHI-3B D- murine myelomonocytic leukemia cells induced by 1 nM 1,25D3 or its low-calcemic analog, 1,25-dihydroxy-16-ene-5,6-trans-cholecalciferol (Ro25-4020), can be synergistically potentiated by carnosic acid (10 μM) or the carnosic acid-rich ethanolic extract of rosemary leaves. This effect was accompanied by cell cycle arrest in G0+G1 phase and a marked inhibition of cell growth. In the in vivo studies, i.p._injections of 2 μg Ro25-4020 in Balb/c mice bearing WEHI-3B D- tumors produced a significant delay in tumor appearance and reduction in tumor size, without significant toxicity. Another analog, 1,25-dihydroxy-16,23Z-diene-20-epi-26,27-hexafluoro-19-nor-cholecalciferol (Ro26-3884) administered at the same dose was less effective than Ro25-4020 and profoundly toxic. Importantly, combined treatment with 1{\%} dry rosemary extract (mixed with food) and 1 μg Ro25-4020 resulted in a strong cooperative antitumor effect, without inducing hypercalcemia. These results indicate for the first time that a plant polyphenolic preparation and a vitamin D derivative can cooperate not only in inducing leukemia cell differentiation in vitro, but also in the antileukemic activity in vivo. These data may suggest novel protocols for chemoprevention or differentiation therapy of myeloid leukemia.",
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AU - Sharoni, Yoav

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