Enhancement by other compounds of the anti-cancer activity of vitamin D3 and its analogs

Danilenko, Michael; Studzinski, George P.

doi:10.1016/j.yexcr.2004.04.029

Cited by 52 publications

(22 citation statements)

References 213 publications

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“…AML blasts and cell lines derived from them can be induced to differentiate by several compounds including VDDs, alone or in combination [11, 16, 25–27]. However, cell differentiation may be masked by cytotoxicity, particularly for the determination of cell surface protein markers such as CD11b and CD14.…”

Section: Resultsmentioning

confidence: 99%

The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts

2016

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Acute Myeloid Leukemia (AML) has grave prognosis due to aggressive nature of the disease, the toxicity of standard treatment, and overall low cure rates. We recently showed that AML cells in established culture treated with cytarabine (AraC) and a differentiation agent combination show enhancement of AraC cytotoxicity. Here we elucidate molecular changes which underlie this observation with focus on AML blasts in primary culture. The cells were treated with AraC at concentrations achievable in clinical settings, and followed by the addition of Doxercalciferol, a vitamin D2 derivative (D2), together with Carnosic acid (CA), a plant-derived antioxidant. Importantly, although AraC is also toxic to normal bone marrow cell population, the enhanced cell kill by D2/CA was limited to malignant blasts. This enhancement of cell death was associated with activation of the monocytic differentiation program as shown by molecular markers, and the increased expression of vitamin D receptor (VDR). Apoptosis elicited by this treatment is caspase-dependent, and the optimal blast killing required the increased expression of the apoptosis regulator Bim. These data suggest that testing of this regimen in the clinic is warranted.

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Section: Resultsmentioning

confidence: 99%

The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts

2016

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“…1,25(OH) 2 D 3 (calcitriol) and its analogs are known to be agents which exert anticancer activities both alone and by cooperating with anticancer compounds (17,48). In our previous experiments with mouse colon cancer MC38 in vivo , we showed that 1,25(OH) 2 D 3 analogs interact synergistically with 5-FU improving its antitumor and antimetastatic activity, as well as prolonging the survival time of mice.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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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“…The molecular mechanism of the synergistic activity of 1,25D 3 and plant polyphenolic antioxidants against myeloid leukemia cells has been extensively studied in our and other laboratories [7,18,19,20,21,22,23] (see also Danilenko and Studzinski [31] for a recent review). We have shown that in human HL60 cells, 1,25D 3 and carnosic acid cooperate in an antioxidant effect and elevation of glutathione levels, whereas glutathione depletion markedly suppressed the differentiation effects of both 1,25D 3 alone and, particularly, its combination with the polyphenol [21].…”

Section: Discussionmentioning

confidence: 99%

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

Shabtay¹,

Sharabani²,

Barvish³

et al. 2008

Oncology

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Objective: Differentiation therapy with the hormonal form of vitamin D, 1α,25-dihydroxyvitamin D₃ (1,25D₃), is a promising approach to treatment of acute myeloid leukemia (AML); however, 1,25D₃ induces hypercalcemia at pharmacologically active doses. We investigated the in vitro and in vivoantileukemic efficacy of combined treatment with non-toxic doses of a low-calcemic 1,25D₃ analogue, 1,25-dihydroxy-21(3-hydroxy-3-methyl-butyl)-19-nor-cholecalciferol (19-nor-Gemini; Ro27-5646), and rosemary plant agents in a mouse model of AML. Methods: Proliferation and differentiation of WEHI-3B D– (WEHI) murine myelomonocytic leukemia cellsin vitro were determined by standard assays. Reactive oxygen species, glutathione and protein expression levels were measured by flow cytometry, enzymatic assay and Western blotting, respectively. Systemic AML was developed by intravenous injection of WEHI cells in syngeneic Balb/c mice. Results: 19-nor-Gemini had a higher potency than its parent compounds, Gemini (Ro27-2310) and 1,25D₃, in the induction of differentiation (EC₅₀ = 0.059 ± 0.011, 0.275 ± 0.093 and 0.652 ± 0.085 nM, respectively) and growth arrest (IC₅₀ = 0.072 ± 0.018, 0.165 ± 0.061 and 0.895 ± 0.144 nM, respectively) in WEHI cells in vitro, and lower in vivo toxicity. Combined treatment of leukemia-bearing mice with 19-nor-Gemini (injected intraperitoneally) and standardized rosemary extract (mixed with food) resulted in a synergistic increase in survival (from 42.2 ± 2.5 days in untreated mice to 66.5 ± 4.2 days, n = 3) and normalization of white blood cell and differential counts. This was consistent with strong cooperative antiproliferative and differentiation effects of low concentrations of 19-nor-Gemini or 1,25D₃ combined with rosemary extract or its major polyphenolic component, carnosic acid, as well as with the antioxidant action of rosemary agents and vitamin D derivatives in WEHI cell cultures. Conclusion: Combined effectiveness of 1,25D₃ analogues and rosemary agents against mouse AML warrants further exploration of this therapeutic approach in translational models of human leukemia.

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Enhancement by other compounds of the anti-cancer activity of vitamin D3 and its analogs

Cited by 52 publications

References 213 publications

The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts

The role of VDR and BIM in potentiation of cytarabine-induced cell death in human AML blasts

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

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

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