Resveratrol selectively inhibits leukemia cells: a prospective agent for ex vivo bone marrow purging

Sc, Gautam; Xu, Yang; Dumaguin, M; Janakiraman, Nalini; Chapman, R.

doi:10.1038/sj.bmt.1702189

Cited by 100 publications

(71 citation statements)

References 20 publications

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“…22 Furthermore, mouse and human leukemic cells selectively undergo apoptosis under resveratrol, while hematopoietic progenitor cells and differentiated cells are largely resistant. 20,23 However, different cell types and even the same cell lines have produced conflicting results with regard to the effects of resveratrol. In the human HL60 promyelocytic leukemia cell line, the drug has been variably reported to induce apoptosis, 24 differentiation 2 and differentiation with S/G 2 arrest without apoptosis.…”

Section: Epithelial Differentiation At Early Times During Resveratrolmentioning

confidence: 99%

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

et al. 2001

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Resveratrol, a polyphenol present in wine and grapes, can inhibit tumor cell growth in vitro and tumorigenesis in vivo. Some of its effects have been linked to activation of the p53 tumor suppressor; however, p53 is frequently mutated in tumors, particularly in the common and often therapy-resistant colon cancers. Using the human wild-type p53-expressing HCT116 colon carcinoma cell line and HCT116 cells with both p53 alleles inactivated by homologous recombination, we show in the current study that resveratrol at concentrations comparable to those found in some foods can induce apoptosis independently of p53. The cell death is primarily mitochondria-mediated and not receptor-mediated. No cells survived in cultures continuously exposed to 100 M resveratrol for 120 hr. When compared with 5-FU, resveratrol stimulated p53 accumulation and activity only weakly and with delayed kinetics and neither the increased levels nor the activity affected apoptosis detectably. The apoptosis agonist Bax was overproduced in response to resveratrol regardless of p53 status, yet the kinetics of Bax expression were influenced by p53. Remarkably, apoptosis was preceded by mitochondrial proliferation and signs of epithelial differentiation. Thus, resveratrol triggers a p53-independent apoptotic pathway in HCT116 cells that may be linked to differentiation. The antifungal phytoalexin resveratrol (3,5,4Ј-trihydroxy-transstilbene) is a constituent of many plant species and present at particularly high levels in grapes and wine. 1 As a polyphenol, it is not only a potent inhibitor of radical formation (ED 50 27 M) but acts as a pleiotropic effector molecule to inhibit initiation, promotion and progression of malignant transformation. Resveratrol inhibits the cyclooxygenase (ED 50 15 M) and hydroperoxidase (ED 50 3.7 M) activities of COX-1 and the hydroperoxidase activity of COX-2 (ED 50 85 M). 2 Furthermore, it functions as an inhibitor of platelet aggregation, a modulator of lipid and lipoprotein metabolism 3 and an effective blocker of ribonucleotide reductase (ED 50 100 M) that provides deoxyribonucleotides for DNA synthesis. 4 It also inhibits DNA polymerase 5 and mimics estradiol. 6 Several of these activities constitute the basis for the chemopreventive action of resveratrol, exemplified by its antimutagenic activity in the Ames assay, inhibition of tumorigenesis in a 2-stage murine skin-cancer model 2 and inhibition of cell proliferation in vitro. 7,8 The presence of the functional wild-type form of the p53 tumor suppressor correlates with the sensitivity of mouse tumors and at least some human tumors to therapeutic agents. 9 -11 p53 is stabilized and activated as a transcription factor in response to a variety of cellular stresses, 12 the result being either cell-cycle arrest, mostly through transcriptional activation of the p21 WAF/Cip1 inhibitor of cyclin-dependent kinases, or apoptosis, depending on the cell context. Apoptosis often involves changes to mitochondria. 13 One of the major predictive parameters indicating commitment...

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Section: Epithelial Differentiation At Early Times During Resveratrolmentioning

confidence: 99%

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

et al. 2001

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“…However, it still has its limitation of high relapse rate, as compared with Allo-HSCT and the limitation is ascribed to the risk of reinfusing residual leukemic cells at the time of harvest. [5][6][7] Several studies on animals have indicated that it is necessary to purge leukemic cells from the bone marrow ex vivo prior to transplantation. [8][9][10][11][12] Therefore, it is essential to eradicate selectively the leukemic cells from grafts for the application of auto-HSCT in leukemia.…”

Section: Introductionmentioning

confidence: 99%

Purging of murine erythroblastic leukemia by ZnPcS2P2-based-photodynamic therapy

Huang

Chen

et al. 2005

Bone Marrow Transplant

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A key point for successful transplantation of autologous hematopoietic stem cells in the treatment of leukemia is the purging technique, of which photodynamic therapy (PDT) proved effective and promising. The aim of this study was to evaluate the purging effect of a novel amphipathic photosensitizer, di-sulfo-di-phthalimidomethyl phthalolcyanine zinc (ZnPcS 2 P 2 )-based PDT (ZnPcS 2 P 2 -PDT) on murine erythroblastic leukemic EL9611 cells. Bone marrow cells (BMC), harvested from normal BALB/c mice, were contaminated with variable EL9611 cells. Cell suspensions were incubated with 4 lg/ml ZnPcS 2 P 2 for 5 h and then exposed to 2.1 J/cm 2 irradiation by a semiconductor laser 670 nm. Lethally irradiated recipient BALB/c mice (7 Gy) received syngeneic bone marrow transplantation with purged or nonpurged cell mixtures of 10 7 BMC contaminated with variable numbers (10 2 -10 5 ) of EL9611 cells. All of the irradiated controls died due to sepsis. All of the mice injected with nonpurged cell mixtures developed leukemia and died, whereas the mice transplanted with ZnPcS 2 P 2 -PDT-treated mixtures had a longer survival time, and the fewer leukemic cells there were in the cell mixtures, the higher the leukemia-free survival rate. We conclude that ZnPcS 2 P 2 -PDT could purge leukemic cells from bone marrow autografts but could retain sufficient progenitor cells for the hematopoietic activity.

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“…Resveratrol has recently attracted considerable interest because of its inhibitor activity on multiple cellular events associated with carcinogenesis (Jang et al, 1997;Runqing et al, 1999). Resveratrol has been shown to have potent growth inhibitory effects on various cancer cells such as colonic tumor cells (Schneider et al, 2000), leukemic cells (Gautam et al, 2000;Dorrie et al, 2001), breast and prostate cancer cells (Mitchell et al, 1999;Damianaki et al, 2000), and has been suggested as one of the most promising cancer chemopreventive agents.…”

mentioning

confidence: 99%

Resveratrol derivatives potently induce apoptosis in human promyelocytic leukemia cells

Kang

Park²,

Choi³

et al. 2003

Exp Mol Med

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Resveratrol selectively inhibits leukemia cells: a prospective agent for ex vivo bone marrow purging

Cited by 100 publications

References 20 publications

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

Resveratrol induces colon tumor cell apoptosis independently of p53 and precede by epithelial differentiation, mitochondrial proliferation and membrane potential collapse

Purging of murine erythroblastic leukemia by ZnPcS2P2-based-photodynamic therapy

Resveratrol derivatives potently induce apoptosis in human promyelocytic leukemia cells

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