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

Abstract

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.

Curcumin suppresses HIF1A synthesis and VEGFA release in pituitary adenomas

“…Curcumin potently inhibited HIF1A protein production both in rodent endocrine pituitary tumour cell lines and in cells of different human pituitary adenoma types. This has also been observed for curcumin and its derivatives in a variety of cell lines serving as models of different types of tumours (Bae et al 2006, Thomas et al 2008, Jung et al 2010, Ströfer et al 2011.…”

“…Although the efficacy of curcumin is currently under investigation in several clinical trials, its usage is limited by its poor bioavailability, which is due to very rapid renal excretion and hepatic degradation (Shehzad et al 2010). More stable curcumin derivatives or curcumin-releasing microparticles, which have successfully been applied in recent studies (Thomas et al 2008, Shahani et al 2010, may overcome this problem in the future.…”

Cellular uptake, retention and bioabsorption of HO-3867, a fluorinated curcumin analog with potential antitumor properties

“…[10][11][12][13] Recently, a novel class of curcumin analogs, namely diarylidenylpiperidone (DAP), has been synthesized by incorporating a piperidone ring in the beta-diketone backbone structure, as well as fluorinating the phenyl groups. [14][15][16] In a previous study, we compared the anticancer efficacy of four DAPs, named as H-4073, HO-3867, HO-4318 and HO-4200 with curcumin in a number of cancer as well non-cancerous (healthy) cell lines. 17,18 All four compounds showed substantially higher antiproliferative activity and induction of apoptosis than curcumin in the cell lines tested.…”

Methylseleninic acid downregulates hypoxia‐inducible factor‐1α in invasive prostate cancer

“…Several antitumor agents including EF24 (curcumin analog), 13 glucosamine, 14 apigenin, 15 quercetin, 16 NS398 (Cox-2 inhibitor), 17 doxorubicin (anthracyclin), 18 trichostatin A (histone deacetylase inhibitor) 19 and rapamycin (mTOR inhibitor) 20 have been shown to inhibit HIF-1a in numerous cancer cell types including those of the prostate. These agents may lead to decreased HIF-1a DNA binding, decreased HIF-1a synthesis or decreased HIF-1a transactivation.…”