Cooperative antitumor effects of vitamin D3 derivatives and rosemary preparations in a mouse model of myeloid leukemia.
1alpha,25-dihydroxyvitamin D(3) (1,25D(3)) 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 1,25D(3) 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 1,25D(3) or its low-calcemic analog, 1,25-dihydroxy-16-ene-5,6-trans-cholecalciferol (Ro25-4020), can be synergistically potentiated by carnosic acid (10 microM) 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 microg 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 microg 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.
Sharabani
Hagar
H
Department of Clinical Biochemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Izumchenko
Eugene
E
Wang
Qing
Q
Kreinin
Rita
R
Steiner
Michael
M
Barvish
Zeev
Z
Kafka
Michael
M
Sharoni
Yoav
Y
Levy
Joseph
J
Uskokovic
Milan
M
Studzinski
George P
GP
Danilenko
Michael
M
D045784:Abietanes / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000097:blood; D002762:Cholecalciferol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005419:Flavonoids; D007942:Leukemia, Experimental / Q000097:blood / Q000188:drug therapy*; D007951:Leukemia, Myeloid / Q000188:drug therapy; D015479:Leukemia, Myelomonocytic, Acute / Q000097:blood / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010636:Phenols; D010936:Plant Extracts / Q000009:adverse effects / Q000494:pharmacology*; D028321:Plant Preparations / Q000494:pharmacology; D059808:Polyphenols; D027542:Rosmarinus; D014407:Tumor Cells, Cultured
C116777:1,25-dihydroxy-16,23-diene vitamin D3; D045784:Abietanes; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D005419:Flavonoids; D010636:Phenols; D010936:Plant Extracts; D028321:Plant Preparations; D059808:Polyphenols; D002762:Cholecalciferol; C018381:salvin; D002118:Calcium