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

Dayton, Alex; Selvendiran, Karuppaiyah; Kuppusamy, M. Lakshmi; Rivera, Brian K.; Meduru, Sarath; Kálai, Tamás; Hideg, Kálmán; Kuppusamy, Periannan

doi:10.4161/cbt.10.10.13250

Cited by 37 publications

(46 citation statements)

References 23 publications

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“…For the EPR study, hOSE and A2780 cells were treated with HO-3867 at 10 μmol/L for 3 hours, and then collected for analysis. The N -hydroxypyrroline (−NOH) moiety is capable of undergoing a reversible, one-electron oxidation to its nitroxide form (−NO · ), which is paramagnetic and detectable by EPR spectroscopy (12). A substantial amount of the nitroxide form of HO-3867 was detected in both cells using EPR, suggesting that HO-3867 rapidly entered the cells during the 3 hour exposure period (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…S8). To confirm uptake of HO-3867, tumor tissues and organs from HO-3867 treated and untreated mice were collected and prepared for EPR spectroscopic analysis as described previously (12). Clear, triplet signals indicating the presence of the −NO · radical (nitroxide) form of HO-3867 were obtained from liver, ovary, kidney, and spleen tissues.…”

Section: Resultsmentioning

confidence: 99%

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HO-3867, a Safe STAT3 Inhibitor, Is Selectively Cytotoxic to Ovarian Cancer

et al. 2014

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STAT3 is well corroborated preclinically as a cancer therapeutic target, but tractable translational strategies for its blockade by small molecule inhibitors have remained elusive. In this study, we report the development of a novel class of bifunctional STAT3 inhibitors, based on conjugation of a diarylidenyl-piperidone (DAP) backbone to an N-hydroxypyrroline (−NOH) group, which exhibits minimal toxicity against normal cells and good oral bioavailability. Molecular modeling studies of this class suggested direct interaction with the STAT3 DNA binding domain. In particular, the DAP compound HO-3867 selectively inhibited STAT3 phosphorylation, transcription, and DNA binding without affecting the expression of other active STATs. HO-3867 exhibited minimal toxicity toward noncancerous cells and tissues but induced apoptosis in ovarian cancer cells. Pharmacologic analysis revealed greater bioabsorption and bioavailability of the active (cytotoxic) metabolites in cancer cells compared with normal cells. The selective cytotoxicity of HO-3867 seemed to be multifaceted, eliciting differential activation of the Akt pathway in normal versus cancer cells. RNAi attenuation experiments confirmed the requirement of STAT3 for HO-3867–mediated apoptosis in ovarian cancer cells. In vivo testing showed that HO-3867 could block xenograft tumor growth without toxic side effects. Furthermore, in primary human ovarian cancer cells isolated from patient ascites, HO-3867 inhibited cell migration/invasion and survival. Our results offer preclinical proof-of-concept for HO-3867 as a selective STAT3 inhibitor to treat ovarian cancer and other solid tumors where STAT3 is widely upregulated.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

HO-3867, a Safe STAT3 Inhibitor, Is Selectively Cytotoxic to Ovarian Cancer

et al. 2014

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“…Efforts have been made to improve curcumin's bioavailability, for example, with the use of structural analogs. 15 Recently, we developed a novel class of curcumin analogs, diarylidenyl piperidones (DAP), which were developed by incorporating a piperidone link to the β-diketone structure and fluorosubstitutions on the phenyl groups. [16][17][18] The DAP compounds, in general, were more effective than curcumin in inhibiting the proliferation of a variety of cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells

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Cohn

et al. 2012

Cancer Biology & Therapy

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“…EF-24, HO-3867) were reported to have increased bioavailability when compared to curcumin and are more effective than curcumin at suppressing tumor growth. 50,51 Interestingly, following an intraperitoneal administration of HO-3867 in rats, the synthetic curcumin analog was detected in the blood, liver, stomach and kidney.…”

Section: Discussionmentioning

confidence: 99%