The semisynthetic flavonoid monoHER sensitises human soft tissue sarcoma cells to doxorubicin-induced apoptosis via inhibition of nuclear factor-κB

Jacobs, H. K.; Bast, Aalt; Peters, Godefridus J.; Vijgh, W.J.F. van der; Haenen, Guido R.M.M.

doi:10.1038/sj.bjc.6606065

Cited by 17 publications

(7 citation statements)

References 24 publications

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“…This may be through its ability to reduce production of the cardiotoxic metabolite DOXOL. MonoHER has also been shown to potentiate the cytotoxicity of DOX in human liposarcoma cells by reducing NF-κB activation and promoting DOX-induced apoptosis [ 143 ]. In vitro and in vivo experiments have shown that monoHER does not interfere with the anti-tumor effect of DOX.…”

Section: Strategies To Improve Clinical Response And/or Reduce Clinicmentioning

confidence: 99%

Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines

Edwardson¹,

Narendrula²,

Chewchuk³

et al. 2015

CDM

110

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Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects. However, this is not the case for the anthracycline class of chemotherapy drugs. This review describes the various enzymes involved in the one electron (semi-quinone) or two electron (hydroxylation) reduction of anthracyclines, or in their reductive deglycosidation into deoxyaglycones. The effects of these reductions on drug anti-tumor efficacy and toxic side effects are also discussed. Current evidence suggests that the one electron reduction of anthracyclines augments both their tumor toxicity and their toxicity towards the host, in particular their cardiotoxicity. In contrast, the two electron reduction (hydroxylation) of anthracyclines strongly reduces their ability to kill tumor cells, while augmenting cardiotoxicity through their accumulation within cardiomyocytes and their direct effects on excitation/contraction coupling within the myocytes. The reductive deglycosidation of anthracyclines appears to inactivate the drug and only occurs under rare, anaerobic conditions. This knowledge has resulted in the identification of important new approaches to improve the therapeutic index of anthracyclines, in particular by inhibiting their cardiotoxocity. The true utility of these approaches in the management of cancer patients undergoing anthracycline-based chemotherapy remains unclear, although one such agent (the iron chelator dexrazoxane) has recently been approved for clinical use.

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Section: Strategies To Improve Clinical Response And/or Reduce Clinicmentioning

confidence: 99%

Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines

Edwardson¹,

Narendrula²,

Chewchuk³

et al. 2015

CDM

110

View full text Add to dashboard Cite

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“…Targeting NF-κB signaling pathways might thus be effective in treating Ras-mutated tumors. Interestingly, NF-κB inhibition by dehydroxymethylepoxyquinomicin inhibited proliferation, decreased mitotic index, and triggered apoptosis of OS cells (Castro-Gamero et al 2012), while the semisynthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside potentiated the antitumor activity of doxorubicin in human LS cells (Jacobs et al 2011).…”

Section: Pathobiologymentioning

confidence: 99%

“…Interestingly, the antimicrobial fish peptide pardaxin exhibited antitumor activity toward murine FS by downregulating STAT-3 and p65/RelA (Wu et al 2012). A clinical phase II study with metastatic cancer patients, evaluating the protective effects of the semisynthetic flavonoid 7mono-O-(β-hydroxyethyl)-rutoside on doxorubicin-induced cardiotoxicity, revealed a 75 % response rate in STS patients (Bruynzeel et al 2007), most probably via inhibition of NF-κB (Jacobs et al 2011). Curcumin from turmeric inhibited growth of LMS and OS cells via inhibition of PI3K/AKT/mTOR and Notch-1, respectively (Wong et al 2011;Li et al 2012b) and induced apoptosis and cell cycle arrest in ES cells (Singh et al 2010).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Inflammatory stress and sarcomagenesis: a vicious interplay

Radons

2014

Cell Stress and Chaperones

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Chronic inflammation represents one of the hallmarks of cancer, but its role in sarcomagenesis has long been overlooked. Sarcomas are a rare and heterogeneous group of tumors of mesenchymal origin accounting for less than 1 % of cancers in adults but 21 % of cancers in the pediatric population. Sarcomas are associated with bad prognosis, and their management requires a multidisciplinary team approach. Several lines of evidence indicate that inflammation has been implicated in sarcomagenesis leading to the activation of the key transcription factors HIF-1, NF- κB, and STAT-3 involved in a complex inflammatory network. In the past years, an increasing number of new targets have been identified in the treatment of sarcomas leading to the development of new drugs that aim to interrupt the vicious connection between inflammation and sarcomagenesis. This article makes a brief overview of preclinical and clinical evidence of the molecular pathways involved in the inflammatory stress response in sarcomagenesis and the most targeted therapies.

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“…This has not been observed in animals thus far 15 . MonoHER has been shown to sensitize cancer cells to apoptosis by preventing doxorubicin‐induced NF‐κB activation 40 . The possible contribution of metabolites to this potentiating effect of monoHER has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Differences in Pharmacological Activities of the Antioxidant Flavonoid MonoHER in Humans and Mice Are Caused by Variations in Its Metabolic Profile

Jacobs

Koek

Peters

et al. 2011

Clin Pharmacol Ther

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Despite its well-known cardiotoxicity, the anthracycline doxorubicin continues to be a widely used chemotherapeutic agent. The flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER) has shown protection against doxorubicin-induced cardiotoxicity in mice. However, this protection has not been observed in humans. This prompted us to investigate monoHER metabolism in humans and compare it with that in mice. Five healthy volunteers received monoHER by intravenous infusion. After infusion, bile fluid was collected, and the monoHER metabolites were identified by liquid chromatography-diode-array detection (LC-DAD), time-of-flight mass spectrometry (TOF-MS), and (1)H-nuclear magnetic resonance (NMR). Thirteen different metabolites were identified. MonoHER was predominantly converted into inactive glucuronidated metabolites. In mice, the major metabolic route is methylation, which forms bioactive metabolites that are implicated in the cardioprotective effect of monoHER. This indicates that the different pharmacological effects of monoHER in mice and humans might be explained by a difference in monoHER metabolism. This study adds to the growing appreciation of flavonoid metabolites as bioactive compounds.

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The semisynthetic flavonoid monoHER sensitises human soft tissue sarcoma cells to doxorubicin-induced apoptosis via inhibition of nuclear factor-κB

Cited by 17 publications

References 24 publications

Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines

Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines

Inflammatory stress and sarcomagenesis: a vicious interplay

Differences in Pharmacological Activities of the Antioxidant Flavonoid MonoHER in Humans and Mice Are Caused by Variations in Its Metabolic Profile

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