Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents

Adams, Brian K.; Ferstl, Eva M.; Davis, Matthew C.; Herold, Marike; Kurtkaya, Serdar; Camalier, Richard F.; Hollingshead, Melinda G.; Kaur, Gurmeet; Sausville, Edward A.; Rickles, Frederick R.; Snyder, James P.; Liotta, Dennis; Miyake, Shoji

doi:10.1016/j.bmc.2004.05.006

Cited by 358 publications

(345 citation statements)

References 38 publications

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“…EF24 was synthesized as previously described. 10 Stock solutions (0.01 mM) were made in dimethyl sulfoxide (DMSO) and stored in aliquots at 4°C. The compounds were diluted in cell culture medium immediately prior to each experiment.…”

Section: Methodsmentioning

confidence: 99%

“…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%

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

Thomas

Zhong²,

Zhou³

et al. 2008

Cell Cycle

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111

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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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Section: Methodsmentioning

confidence: 99%

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

111

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“…A curcumin analogue, EF24, was discovered to be more active [15] than its parent compound. To improve the solubility and activity further, we replace the 2-fluorinebenzyl group on EF24 with 3-pyridine to obtain the C817 molecule [16] ( Figure 1A).…”

Section: Reagentsmentioning

confidence: 99%

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

Wāng

Chen

et al. 2014

Acta Pharmacol Sin

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Aim: To find new kinase inhibitors that overcome the imatinib resistance in treatment of chronic myeloid leukemia (CML), we synthesized C817, a novel derivative of curcumin, and tested its activities against wild-type (WT) and imatinib-resistant mutant Abl kinases, as well as in imatinib-sensitive and resistant CML cells in vitro. Methods: 32D cells harboring WT or mutant Abl kinases (nucleotide binding P-loop mutants Q252H, Y253F, and imatinib contact residue mutant T315I), as well as K562/G01 cells (with whole Bcr-Abl gene amplication) were tested. Kinase activity was measured using Kinase-Glo Luminescent Kinase Assay Platform in recombinant WT and mutant (Q252H, Y253F, and T315I) Abl kinases. Cell proliferation and apoptosis were examined using MTT assay and flow cytometry, respectively. The phosphorylation levels of Bcr-Abl initiated signaling proteins were analyzed using Western blotting. Colony forming units (CFU) growth and long term culture-initiating cells (LTC-ICs) were used to test the effects of C817 on human leukemia progenitor/stem cells. Results: C817 potently inhibited both WT and mutant (Q252H, Y253F, and T315I) Abl kinase activities in a non-ATP competitive manner with the values of IC 50 at low nanomole levels. In consistent with above results, C817 suppressed the growth of both imatinib-sensitive and resistant CML cells, including wild-type K562, K562/G01, 32D-T315I, 32D-Q252H, and 32D-Y253F cells with the values of IC 50 at low micromole levels. C817 (0.5 or 1 μmol/L) dose-dependently inhibited the phosphorylation of Bcr-Abl and downstream proteins STAT-5 and CrkL in imatinib-resistant K562/G01 cells. Furthermore, C817 significantly suppressed CFU growth and LTC-ICs, implicating that C817 could eradiate human leukemia progenitor/stem cells. Conclusion: C817 is a promising compound for treatment of CML patients with Bcr-Abl kinase domain mutations that confer imatinib resistance.

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“…[1][2][3][4] Among these attractive properties, we are particularly interested in the potential of bis(arylmethylidene)acetones as anticancer chemotherapeutic agents. Thus, we have synthesized more than 100 bis(arylmethylidene)acetones and tested them for their ability to inhibit cancer cell growth.…”

mentioning

confidence: 99%

KSRP/FUBP2 Is a Binding Protein of GO-Y086, a Cytotoxic Curcumin Analogue

Yamakoshi

Kanoh

Kudo

et al. 2010

ACS Med. Chem. Lett.

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Bis(arylmethylidene)acetone derivatives are an important class of curcumin analogues that exhibit various biological and pharmacological activities. We herein report that GO-Y086, a biotinylated bis(arylmethylidene)acetone, inhibits cancer cell growth. We also show that GO-Y086 specifically interacts with the nuclear protein KSRP/FUBP2 by covalent modification. GO-Y086 markedly suppresses the expression of the c-Myc protein, which plays an important role in cellular proliferation and whose expression is regulated by KSRP/FUBP2.

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Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents

Cited by 358 publications

References 38 publications

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

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

Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro

KSRP/FUBP2 Is a Binding Protein of GO-Y086, a Cytotoxic Curcumin Analogue

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