Cyclin D3 and p53 mediate sulforaphane-induced cell cycle delay and apoptosis in non-transformed human T lymphocytes

Fimognari, Carmela; Nüsse, Michael; Berti, Fausto; Iori, Renato; Cantelli‐Forti, Giorgio; Hrelia, Patrizia

doi:10.1007/pl00012523

Cited by 42 publications

(23 citation statements)

References 32 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One possibility involves the inhibition of cell proliferation. It was previously demonstrated that the treatment of human lymphocytes with 3, 10 and 30 mM sulforaphane induces a block in cell-cycle progression through an accumulation of cells in G 1 phase [Fimognari et al, 2002b]. We postulate that treatment with sulforaphane delays cell-cycle progression, thus reducing the number of cells reaching M phase, on which VIN acts.…”

Section: Discussionmentioning

confidence: 93%

Effect of sulforaphane on micronucleus induction in cultured human lymphocytes by four different mutagens

Fimognari

Berti

Cantelli‐Forti

et al. 2005

Environ. Mol. Mutagen.

View full text Add to dashboard Cite

Isothiocyanates (ITCs) are commonly found in cruciferous vegetables. A variety of biological activities have been ascribed to ITCs, such as inhibition of cytochrome P450 enzymes and induction of phase II enzymes in animal models. ITCs are also able to block cell-cycle progression and induce apoptosis in human cancer cells in vitro. In this study, we evaluated the ability of the ITC sulforaphane to protect cultured human lymphocytes from micronucleus (MN) induction by four different mutagens: ethyl methanesulfonate (EMS), vincristrine (VIN), H(2)O(2) and mitomycin C (MMC). To understand the mechanisms of action of sulforaphane, the cultures were treated with the compound before, during and after treatment with the mutagens; in addition, the cultures were evaluated for the induction of apoptosis. Up to 10 microM, sulforaphane was non-genotoxic by itself, while 30 microM sulforaphane reduced the replicative index of the cells by more than 60%. Moreover, 1-10 microM sulforaphane reduced the MN frequency induced by EMS, VIN, H(2)O(2) and MMC in at least one of the treatment protocols; it had no effect on H(2)O(2)-MN induction in the post-treatment protocol, and it increased MN induction by MMC in the pre-treatment protocol. Apoptosis was produced in the cultures treated with sulforaphane alone. The fraction of apoptotic cells was increased after co- or post-treatment with sulforaphane and EMS and MMC, suggesting that sulforaphane-mediated apoptosis may remove highly damaged cells induced by these agents. Other mechanisms are involved in the anti-genotoxic activity of sulforaphane against VIN and H(2)O(2). Taken together, our findings indicate that under certain conditions sulforaphane possesses anti-genotoxic activity in vitro and that further studies are warranted to characterize this property in vivo.

show abstract

Section: Discussionmentioning

confidence: 93%

Effect of sulforaphane on micronucleus induction in cultured human lymphocytes by four different mutagens

Fimognari

Berti

Cantelli‐Forti

et al. 2005

Environ. Mol. Mutagen.

View full text Add to dashboard Cite

show abstract

“…An example of such simultaneous membrane signals might be the induction of Fas receptor clustering in Jurkat cells (2). By contrast, the divergent effect of impairing cyclin and cdk activity that leads to cell cycle arrest in A549 or apoptosis in Jurkat cells, may also reflect the downstream crosstalk mechanisms (2,3,(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

Lladó¹,

Terés

Higuera

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

␣-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.anticancer ͉ DNA ͉ membrane-lipid therapy ͉ neoplasia ͉ nutrigenetics 2 -Hydroxyoleic acid (HOA) is a potent anticancer drug whose molecular mechanism of action is still not fully understood. Although HOA induces cell cycle exit in human lung cancer (A549) cells (1), it induces apoptosis in human leukemia cells (2). The IC 50 of this drug for most cancer cells studied is in the range of 30-150 M, whereas its IC 50 in normal cells is over 5,000 M (2). Thus, this drug does not produce toxicity at therapeutic doses despite acting efficiently in cell and animal models of human cancers (2, 3). Hence, it is important to define the mode of action of this compound and whether common molecular events underlie its therapeutic effects and the regression of different types of cancer.HOA was developed on the basis that the lipid composition and structure of the plasma membrane can be altered by certain antitumor drugs and that these modifications are involved in their action against cancer (4, 5). In this context, anthracyclines that are unable to enter cancer cells or bind to DNA still have strong antitumor activity (6). Indeed, those used in human therapy regulate plasma membrane structure, and they induce changes in the localization and activity of important peripheral signaling proteins, such as G proteins and PKC (4,7,8). This mode of action also appears to be responsible for the activity of hexamethylene bisacetamide against cancers (9, 10).In the search for molecules capable of i...

show abstract

“…The involvement of p53 in SF-mediated apoptosis is not clear. Reports from Fimognari and colleagues suggest that SF treatment increased the expression of p53 protein in non-transformed human T lymphocytes [137], and this increase was associated with a significant increase in the protein levels of Bax and a slight decrease in Bcl-2 measured in T cell leukaemia cells [138]. In contrast, levels of p53 and Bcl-2 remained unchanged in response to SF treatment in HT29 cells [110].…”

Section: The Role Of Bcl-2 Family In Sf-mediated Apoptosismentioning

confidence: 97%

Molecular basis for chemoprevention by sulforaphane: a comprehensive review

Juge

Mithen

Τράκα

2007

Cell. Mol. Life Sci.

628

490

View full text Add to dashboard Cite

The consumption of cruciferous vegetables has long been associated with a reduced risk in the occurrence of cancer at various sites, including the prostate, lung, breast and colon. This protective effect is attributed to isothiocyanates present in these vegetables, and sulforaphane (SF), present in broccoli, is by far the most extensively studied to uncover the mechanisms behind this chemoprotection. The major mechanism by which SF protects cells was traditionally thought to be through Nrf2-mediated induction of phase 2 detoxification enzymes that elevate cell defense against oxidative damage and promote the removal of carcinogens. However, it is becoming clear that there are multiple mechanisms activated in response to SF, including suppression of cytochrome P450 enzymes, induction of apoptotic pathways, suppression of cell cycle progression, inhibition of angiogenesis and anti-inflammatory activity. Moreover, these mechanisms seem to have some degree of interaction to synergistically afford chemoprevention.

show abstract

Cyclin D3 and p53 mediate sulforaphane-induced cell cycle delay and apoptosis in non-transformed human T lymphocytes

Cited by 42 publications

References 32 publications

Effect of sulforaphane on micronucleus induction in cultured human lymphocytes by four different mutagens

Effect of sulforaphane on micronucleus induction in cultured human lymphocytes by four different mutagens

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

Molecular basis for chemoprevention by sulforaphane: a comprehensive review

Contact Info

Product

Resources

About