Therapeutic role of <scp>EF</scp>24 targeting glucose transporter 1‐mediated metabolism and metastasis in ovarian cancer cells

Zhang, Dandan; Wang, Yan; Liu, Dong; Huang, Yangang; Yuan, Jing; Ben, Wei; Yang, Yang; Ning, Ning; Lu, Meisong; Guan, Yongmei

doi:10.1111/cas.12293

Cited by 31 publications

(26 citation statements)

References 26 publications

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“…As described earlier, one crucial question in glycoconjugate chemistry is whether or not the sugar-conjugated molecule is actually transported by the targeted sugar transporters.T oa ddress this issue,w ec arried out as eries of experiments to investigate the details of the mechanism by which 1-3 are taken up by cells.G lc-Pts 1-3 are very hydrophilic (log P %À2) rendering cellular internalization by passive diffusion through the cellular lipid membrane highly unlikely.F urthermore,t he lack of correlation between the log P values and cellular uptake is consistent with ap roteinmediated transport mechanism ( Figure S10a). Theo varian cancer cell line A2780 was chosen to evaluate the cellular uptake mechanism of the Glc-Pts because of its high level of GLUT1 expression, [17] confirmed by immunoblotting analyses ( Figure S10b). Cellular uptake was first monitored in the absence and presence of an exofacial GLUT1 inhibitor 4,6-Oethylidene-a-d-glucose (EDG), [18] and the results are presented in Figures 2a and S14c.…”

Section: Angewandte Chemiementioning

confidence: 99%

A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

2016

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Three rationally designed glucose-platinum conjugates (Glc-Pts) were synthesized and their biological activities evaluated. The Glc-Pts, 1-3,exhibit high levels of cytotoxicity towardapanel of cancer cells.T he subcellular target and cellular uptake mechanism of the Glc-Pts were elucidated. For uptake into cells,G lc-Pt 1 exploits both glucose and organic cation transporters,b oth widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer,compared to normal epithelial, cells in vitro.Platinum-basedanticancerdrugs are among the most widely used of all chemotherapeutic treatments.T hree FDAapproved platinum anticancer drugs,c isplatin, carboplatin, and oxaliplatin, have been in the clinic for many years to treat av ariety of cancers including testicular,o varian, cervical, head and neck, non-small-cell lung, and colorectal. [1] Despite their success,p latinum compounds have an umber of deficiencies originating from al ack of tumor selectivity.O nly as mall fraction of the total administered platinum accumulates at the tumor site,r esulting in sub-optimal drug concentration at the target. Moreover,a ccumulation of platinum in healthy tissue leads to undesired side effects including nephrotoxicity,m yelosuppression, peripheral neuropathy, ototoxicity,a nd nausea. [1b, 2] These drawbacks need to be addressed when designing next-generation platinum drugs. Novel strategies for introducing tumor-targeting properties into platinum anticancer drug candidates are therefore of great interest. [3] In order to maintain cellular homeostasis,g rowth, and proliferation, cancer cells significantly increaseglucose uptake andt he fluxo fm etabolites throughg lycolysis.T his phenomenon, termed "the Warburg effect", arisesfrommitochondrial metabolic changesa nd is one of the hallmarkso fc ancer. [4] GLUT1,t he mostc ommon glucose transporter, is widely overexpressed in manyh uman cancersi ncludingh epatic, pancreatic,b reast,e sophageal, brain, renal, lung,c utaneous, colorectal, endometrial, ovarian,and cervical. [5] HighGLUT1 expressionl evelsi nt umor biopsy samples correlates trongly withp oorp rognosis. Moreover,s everalo ther glucose transporters including GLUT2,G LUT3,G LUT12,a nd SGLT1/2[*] Dr.

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Section: Angewandte Chemiementioning

confidence: 99%

A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

2016

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“…Similar encouraging results for EF24 ( 6 ) have been observed in the recent past for both subcutaneous and orthotopic hepatocellular carcinoma (HCC) models [ 111 ]. DU145 prostate cancer xenografts in immunocompromised mice [ 112 ] energy metabolism and ovarian cancer metastasis models [ 113 ] ovarian carcinoma xenografts [ 114 ] and potent growth inhibition (GI 50 ) of a HCT-116 human colon tumor xenograft in mice with little apparent toxicity [ 115 , 116 ]. As a companion to these murine studies, comprehensive pre-clinical mouse pharmacokinetics and metabolism have been performed for EF24 ( 6 ) by application of an LC/MS/MS assay [ 18 ].…”

Section: Cancer Mediation In Vitro and mentioning

confidence: 99%

Eliminating the Heart from the Curcumin Molecule: Monocarbonyl Curcumin Mimics (MACs)

et al. 2014

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Curcumin is a natural product with several thousand years of heritage. Its traditional Asian application to human ailments has been subjected in recent decades to worldwide pharmacological, biochemical and clinical investigations. Curcumin’s Achilles heel lies in its poor aqueous solubility and rapid degradation at pH ~ 7.4. Researchers have sought to unlock curcumin’s assets by chemical manipulation. One class of molecules under scrutiny are the monocarbonyl analogs of curcumin (MACs). A thousand plus such agents have been created and tested primarily against cancer and inflammation. The outcome is clear. In vitro, MACs furnish a 10–20 fold potency gain vs. curcumin for numerous cancer cell lines and cellular proteins. Similarly, MACs have successfully demonstrated better pharmacokinetic (PK) profiles in mice and greater tumor regression in cancer xenografts in vivo than curcumin. The compounds reveal limited toxicity as measured by murine weight gain and histopathological assessment. To our knowledge, MAC members have not yet been monitored in larger animals or humans. However, Phase 1 clinical trials are certainly on the horizon. The present review focuses on the large and evolving body of work in cancer and inflammation, but also covers MAC structural diversity and early discovery for treatment of bacteria, tuberculosis, Alzheimer’s disease and malaria.

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“…EF24 has a higher cytotoxic potency than cisplatin on CAL-27 cells. Previous studies have demonstrated the cytotoxicity of EF24 in prostate, ovarian and breast cancer cells (11)(12)(13).…”

Section: Resultsmentioning

confidence: 99%

Curcumin analog EF24 induces apoptosis and downregulates the mitogen activated protein kinase/extracellular signal-regulated signaling pathway in oral squamous cell carcinoma

Chen¹,

Tu²,

Ma³

et al. 2017

Molecular Medicine Reports

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Oral squamous cell carcinoma (OSCC) is one of the most common malignancies worldwide. Diphenyldifluoroketone (EF24) is a curcumin analog that has been demonstrated to improve anticancer activity; however, its therapeutic potential and mechanisms in oral cancer remain unknown. In the present study, the effect of EF24 on apoptosis induction and its potential underlying mechanism in the CAL‑27 human OSCC cell line was investigated. To achieve this, various concentrations of cisplatin or EF24 were administrated to CAL‑27 cells for 24 h, and cell viability, apoptotic DNA fragmentation, and cleaved caspase 3 and 9 levels were evaluated. To investigate the potential underlying mechanism, the levels of mitogen‑activated protein kinase kinase 1 (MEK1) and extracellular signal‑regulated kinase (ERK), two key proteins in the mitogen‑activated protein kinase/ERK signaling pathway, were additionally examined. The results indicated that EF24 and cisplatin treatment decreased cell viability. EF24 treatment increased the levels of activated caspase 3 and 9, and decreased the phosphorylated forms of MEK1 and ERK. Sequential treatments of EF24 and 12‑phorbol‑13‑myristate acetate, a MAPK/ERK activator, resulted in a significant increase of activated MEK1 and ERK, and reversed cell viability. These results suggested that EF24 has potent anti‑tumor activity in OSCC via deactivation of the MAPK/ERK signaling pathway. Further analyses using animal models are required to confirm these findings in vivo.

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Therapeutic role of EF24 targeting glucose transporter 1‐mediated metabolism and metastasis in ovarian cancer cells

Cited by 31 publications

References 26 publications

A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

Eliminating the Heart from the Curcumin Molecule: Monocarbonyl Curcumin Mimics (MACs)

Curcumin analog EF24 induces apoptosis and downregulates the mitogen activated protein kinase/extracellular signal-regulated signaling pathway in oral squamous cell carcinoma

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