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

Abstract

1a,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 2 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 lM) or the carnosic acid-rich ethanolic extract of rosemary leaves. This effect was accompanied by cell cycle arrest in G01G1 phase and a marked inhibition of cell growth. In the in vivo studies, i.p. injections of 2 lg Ro25-4020 in Balb/c mice bearing WEHI-3B D 2 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 lg 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.

Upregulation of Akt/NF-κB-regulated inflammation and Akt/Bad-related apoptosis signaling pathway involved in hepatic carcinoma process: suppression by carnosic acid nanoparticle

“…Currently, CA has been reported to have several properties in antitumor, such as colonic cancer, mammary tumors, as well as skin tumors, through regulating cancer cell growth, apoptosis, reactive oxygen species, and also Akt activation. [16][17][18][19][20] And also, previous studies have suggested that nanoparticulate drug delivery systems have been known to better the bioavailability of drugs on intranasal administration compared with only drug solutions. 21,22 In addition, a study has found that nanoparticulate drug delivery system for CA intranasal administration needed less amounts of administrations to induce the required pharmacological reaction due to its ability to locate on the olfactory mucosal region and supply controlled CA delivery for prolonged time periods.…”

“…CA has been suggested to have anticancer effects in colon cancer, acute myeloid leukemia, and skin cancer via anti-inflammation, antioxidant, and antimicrobial effects. [15][16][17][18][19][20] However, the molecular mechanism revealing improving liver cancer remains poorly understood. And few previous studies have reported that nanoparticle of CA could be better absorbed for animals.…”

Differentiation-inducing potency of the seco-steroid JK-1624F2-2 can be increased by combination with an antioxidant and a p38MAPK inhibitor which upregulates the JNK pathway

“…Murine model of myelomonocytic leukemia, WEHI-3B D -cells, were grown in McCoy's 5a medium plus 10% heat-inactivated fetal calf serum (GIBCO-BRL, Gaitherburg, MD) [28]. The cells were passaged and fed with medium 2-3 times per week to maintain the log phase growth.…”

“…The percentage of NSE positive cells in a total of 500 cells was counted using a hemocytometer. Differentiation of WEHI-3B D -cells was determined by the nitroblue tetrazolium (NBT) reduction test, as previously described [28]. To determine the mode of cell death, annexin V and propidium iodide (PI) staining assay was performed (Annexin V-FITC Apoptosis Detection Kit, Sigma).…”

Synergistic Antileukemic Activity of Carnosic Acid-Rich Rosemary Extract and the 19-nor Gemini Vitamin D Analogue in a Mouse Model of Systemic Acute Myeloid Leukemia

“…For example, standard treatment of AML generally includes a synthetic pyrimidine nucleoside cytarabine (Ara-C), which functions as an antimetabolite and DNA polymerase inhibitor, in combination with an anthracycline agent (idarubicin or daunorubicin), which acts as topoisomerase II inhibitor and DNA intercalator [1]. In analogy, the anticancer effects of combinations of vitamin D derivatives (deltanoids) with other agents have been extensively studied in cultures of leukemic cells and other cancer cell types [9,10,11,12], animal models of cancer [13, 14] and clinical trials [15,16,17]. These studies are especially important since combination treatment may allow lower doses of deltanoids, thereby further limiting calcemic toxicity of these compounds.…”