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Cooperative antitumor effects of vitamin D 3 derivatives and rosemary preparations in a mouse model of myeloid leukemia
Author(s) -
Sharabani Hagar,
Izumchenko Eugene,
Wang Qing,
Kreinin Rita,
Steiner Michael,
Barvish Zeev,
Kafka Michael,
Sharoni Yoav,
Levy Joseph,
Uskokovic Milan,
Studzinski George P.,
Danilenko Michael
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21736
Subject(s) - carnosic acid , myeloid leukemia , pharmacology , cholecalciferol , leukemia , myeloid , hl60 , in vivo , cancer research , chemistry , biology , medicine , endocrinology , biochemistry , vitamin d and neurology , microbiology and biotechnology , antioxidant
Abstract 1α,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 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. © 2006 Wiley‐Liss, Inc.