EF24, a novel synthetic curcumin analog, induces apoptosis in cancer cells via a redox-dependent mechanism

Adams, Brian K.; Cai, Jiyang; Armstrong, Jeff; Herold, Marike; Lu, Yang; Sun, Aiming; Snyder, James P.; Liotta, Dennis; Jones, Dean P.; Miyake, Shoji

doi:10.1097/00001813-200503000-00005

Cited by 189 publications

(202 citation statements)

References 39 publications

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“…2,3 Recently, curcumin has become a focus of interest with regard to its possible antitumor effects in prostate cancer. [12][13][14][15][16][17][18] This study shows for the first time, to our knowledge, that curcumin exerts an inhibitory effect on the invasiveness of DU-145 prostate cancer cells, and confirms this via both in vitro and in vivo testing.…”

Section: Discussionsupporting

confidence: 78%

“…The results of previous studies have revealed that curcumin exerts pleiotropic effects on prostate cancer cells; however, its functions in invasion and metastasis have yet to be clearly elucidated. [12][13][14][15][16][17][18] Therefore, we assessed the effects of curcumin on the in vitro invasion of prostate cancer cells (DU-145), and further attempted to determine, using a tumor xenograft model, whether curcumin effected an inhibition of prostate cancer cell invasiveness.…”

Section: Introductionmentioning

confidence: 99%

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The effects of curcumin on the invasiveness of prostate cancer in vitro and in vivo

Hong

Ahn

Bae

et al. 2006

Prostate Cancer Prostatic Dis

152

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Curcumin has become a focus of interest with regard to its antitumor effects in prostate cancer; however, the effects of this agent on invasion and metastasis remain less well understood. Matrix metalloproteinases (MMPs) are important prerequisite for tumor invasion and metastasis. In this study, we evaluated the effects of curcumin on prostate cancer cells (DU-145) invasion in both in vitro and in vivo. We utilized zymography and ELISA in order to determine the MMP-2 and MMP-9 activity. Matrigel invasion assay was performed to assess cellular invasion. We developed a xenograft model to examine tumorigenicity. Curcumin treatment resulted not only in a significant reduction in the expression of MMP-2 and MMP-9, but also effected the inhibition of invasive ability in vitro. Curcumin was shown to induce a marked reduction of tumor volume, MMP-2, and MMP-9 activity in the tumor-bearing site. The metastatic nodules in vivo were significantly fewer in the curcumintreated group than untreated group. Curcumin appears to constitute a potential agent for the prevention of cancer progression, or at least of the initial phase of metastasis, in prostate cancer.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

The effects of curcumin on the invasiveness of prostate cancer in vitro and in vivo

Hong

Ahn

Bae

et al. 2006

Prostate Cancer Prostatic Dis

152

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“…This suggests that formation of curcumin-GSH adducts lead to inactivation of parent curcumin's activity. This is, however, unlikely because glutathionylated curcumin has been reported to be more active than curcumin [57]. We also found that NAC reverses the effect of curcumin, most likely by increasing intracellular GSH contents.…”

Section: Discussionmentioning

confidence: 48%

Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane)

Sandur

Ichikawa

Pandey

et al. 2007

Free Radical Biology and Medicine

272

175

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Extensive research within last half a century has indicated that curcumin (diferuloylmethane), a yellow pigment in curry powder, exhibits antioxidant, anti-inflammatory and proapoptotic activities. Whether anti-inflammatory and proapoptotic activities assigned to curcumin, are mediated through its antioxidant mechanism was investigated. We found that TNF-mediated NF-κB activation was inhibited by curcumin; and glutathione reversed the inhibition. Similarly, suppression of TNFinduced AKT activation by curcumin, was also abrogated by glutathione. The reducing agent also counteracted the inhibitory effect of curcumin on TNF-induced NF-κB regulated antiapoptotic (Bcl-2, Bcl-xL, IAP1), proliferative (cyclin D1) and proinflammatory (COX-2, iNOS and MMP-9) gene products. The suppression of TNF-induced AP-1 activation by curcumin was also reversed by glutathione. Also, the direct proapoptotic effects of curcumin were inhibited by glutathione and potentiated by depletion of intracellular glutathione by buthionine sulfoximine. Moreover, curcumin induced the production of reactive oxygen species (ROS) and modulated the intracellular GSH levels. Quenchers of hydroxyl radicals, however, were ineffective in inhibiting curcumin mediated NF-κB suppression. Further, N-acetylcysteine partially reversed the effect of curcumin. Based on these results we conclude that curcumin mediate its apoptotic and anti-inflammatory activities through modulation of the redox status of the cell.

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“…Importantly, in animal models EF24 has demonstrated a superior pharmacokinetic and activity profile relative to curcumin while remaining well tolerated. 10,11 In addition, the compound inhibits vascular endothelial growth factor-induced angiogenesis in rabbit and mice models and causes significant reduction in tumor size in human breast cancer xenografts in athymic nude mice. 12 In this study, we set out to elucidate aspects of the molecular mechanism of action of EF24.…”

Section: Introductionmentioning

confidence: 99%

EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1

Thomas

Zhong²,

Zhou³

et al. 2008

Cell Cycle

Self Cite

109

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Curcumin, the yellow pigment of the spice turmeric, has emerged as a promising anticancer agent due to its antiproliferative and antiangiogenic properties. However, the molecular mechanism of action of this compound remains a subject of debate. In addition, curcumin's low bioavailability and efficacy profile in vivo further hinders its clinical development. This study focuses on the mechanism of action of EF24, a novel curcumin analog with greater than curcumin biological activity and bioavailability, but no increased toxicity. Treatment of MDA-MB231 breast and PC3 prostate cancer cells with EF24 or curcumin led to inhibition of HIF-1α protein levels and, consequently, inhibition of HIF transcriptional activity. This drug-induced HIF inhibition occurred in a VHL-dependent but proteasome-independent manner. We found that, while curcumin inhibited HIF-1α gene transcription, EF24 exerted its activity by inhibiting HIF-1α posttranscriptionally. This result suggested that the two compounds are structurally similar but mechanistically distinct. Another cellular effect that further differentiated the two compounds was the ability of EF24, but not curcumin, to induce microtubule stabilization in cells. EF24 had no stabilizing effect on tubulin polymerization in an in vitro assay using purified bovine brain tubulin, suggesting that the EF24-induced cytoskeletal disruption in cells may be the result of upstream signaling events rather than EF24 direct binding to tubulin. In summary, our study identifies EF24 as a novel curcumin-related compound possessing a distinct mechanism of action, which we believe contributes to the potent anticancer activity of this agent and can be further exploited to investigate the therapeutic potential of EF24.

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EF24, a novel synthetic curcumin analog, induces apoptosis in cancer cells via a redox-dependent mechanism

Cited by 189 publications

References 39 publications

The effects of curcumin on the invasiveness of prostate cancer in vitro and in vivo

The effects of curcumin on the invasiveness of prostate cancer in vitro and in vivo

Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane)

EF24, a novel curcumin analog, disrupts the microtubule cytoskeleton and inhibits HIF-1

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