Parthenolide: from plant shoots to cancer roots

Ghantous, Akram; Sinjab, Ansam; Herceg, Zdenko; Darwiche, Nadine

doi:10.1016/j.drudis.2013.05.005

Cited by 262 publications

(224 citation statements)

References 75 publications

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“…is also known as a strong NF-B inhibitor (20). However, although we confirmed that 7.5 M PTL induced a loss of p65 electrophoretic mobility shift assay (EMSA) binding activity, a reduction of NF-B p65 phosphorylation, and a decrease in NF-B target gene IL-6 expression, the PDT regimen had no effect on any of these three readouts, indicating that the antileukemic mechanism of PDT is independent of NF-B inhibition (Fig.…”

Section: Pdt Regimen Does Not Affect Nf-b Signaling But Induces Stronmentioning

confidence: 99%

“…As a foundation for rational design of a multidrug regimen, we chose to evaluate parthenolide (PTL), a naturally occurring small molecule with reported anti-tumor properties in nearly all major forms of human cancer (20,21). Of particular interestis the activity of PTL as an agent in AML where it can target bulk tumor cells as well as the relatively rare AML stem cell population (22).…”

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confidence: 99%

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Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Pei¹,

Minhajuddin²,

D’Alessandro

et al. 2016

Journal of Biological Chemistry

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Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens.Numerous studies have documented the biological complexity of human tumor cell populations in which genetic, epigenetic, biochemical, and metabolic properties can often be quite heterogeneous (1, 2). As a result, complicated multidrug regimens are often employed to target various components of tumor biology and/or acquired drug resistance (3, 4). However, the rationale behind the design of multidrug regimens is usually inconsistent and often driven by pragmatism more than scientific rigor. Thus, establishing more effective means by which to identify optimal drug regimens is an important priority, particularly with the recent emergence of a broad range of targeted agents.

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Section: Pdt Regimen Does Not Affect Nf-b Signaling But Induces Stronmentioning

confidence: 99%

mentioning

confidence: 99%

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Pei¹,

Minhajuddin²,

D’Alessandro

et al. 2016

Journal of Biological Chemistry

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“…Phenoxybenzamine is an a-1 adrenoceptor inhibitor and is used as an antihypertensive agent (42). 15-d-PGJ 2 is a peroxisome proliferator-activated receptor g agonist, and parthenolide is an NF-kB inhibitor with anti-inflammatory and antiproliferation activities (43,44). These compounds with connectivity scores .0.85 were first examined for their TLR9 activation inhibitory activities.…”

Section: Identification Of Thiostrepton As a Novel Tlr9 Inhibitormentioning

confidence: 99%

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

Lai

Yeh

et al. 2015

The Journal of Immunology

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Activation of TLR7–9 has been linked to the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Thus, therapeutic applications of antagonists of these TLRs for such disorders are being investigated. Bortezomib (Velcade) is a proteasome inhibitor known to suppress activation of these TLRs. To identify novel TLR7–9 inhibitors, we searched the Gene Expression Omnibus database for gene expression profiles of bortezomib-treated cells. These profiles were then used to screen the Connectivity Map database for chemical compounds with similar functions as bortezomib. A natural antibiotic, thiostrepton, was identified for study. Similar to bortezomib, thiostrepton effectively inhibits TLR7–9 activation in cell-based assays and in dendritic cells. In contrast to bortezomib, thiostrepton does not inhibit NF-κB activation induced by TNF-α, IL-1, and other TLRs, and it is less cytotoxic to dendritic cells. Thiostrepton inhibits TLR9 localization in endosomes for activation via two mechanisms, which distinguish it from currently used TLR7–9 inhibitors. One mechanism is similar to the proteasome inhibitory function of bortezomib, whereas the other is through inhibition of endosomal acidification. Accordingly, in different animal models, thiostrepton attenuated LL37- and imiquimod-induced psoriasis-like inflammation. These results indicated that thiostrepton is a novel TLR7–9 inhibitor, and compared with bortezomib, its inhibitory effect is more specific to these TLRs, suggesting the potential therapeutic applications of thiostrepton on immunologic disorders elicited by inappropriate activation of TLR7–9.

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“…PN is a sesquiterpene lactone, derived from the medicinal plant feverfew Tanacetum parthenium, which is conventionally used to treat migraine and rheumatoid arthritis (1). In addition it has been shown that PN exhibits anticancer activity in several cancer cell types, such as colorectal cancer (2), pancreatic cancer (3), prostate cancer (4), multiple myeloma (5), osteosarcoma and melanoma (6).…”

Section: Introductionmentioning

confidence: 99%

Parthenolide induces superoxide anion production by stimulating EGF receptor in MDA-MB-231 breast cancer cells

D’Anneo¹,

Carlisi²,

Emanuele³

et al. 2013

International Journal of Oncology

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Abstract. The sesquiterpene lactone parthenolide (PN) has recently attracted considerable attention because of its antimicrobial, anti-inflammatory and anticancer effects. However, the mechanism of its cytotoxic action on tumor cells remains scarcely defined. We recently provided evidence that the effect exerted by PN in MDA-MB-231 breast cancer cells was mediated by the production of reactive oxygen species (ROS). The present study shows that PN promoted the phosphorylation of EGF receptor (phospho-EGFR) at Tyr1173, an event which was observed already at 1 h of incubation with 25 µM PN and reached a peak at 8-16 h. This effect seemed to be a consequence of ROS production, because N-acetylcysteine (NAC), a powerful ROS scavenger, prevented the increment of phospho-EGFR levels. In addition fluorescence analyses performed using dihydroethidium demonstrated that PN stimulated the production of superoxide anion already at 2-3 h of incubation and the effect further increased prolonging the time of treatment, reaching a peak at 8-16 h. Superoxide anion production was markedly hampered by apocynin, a well known NADPH oxidase (NOX) inhibitor, suggesting that the effect was dependent on NOX activity. The finding that AG1478, an EGFR kinase inhibitor, substantially blocked both EGFR phosphorylation and superoxide anion production strongly suggested that phosphorylation of EGFR can be responsible for the activation of NOX with the consequent production of superoxide anion. Therefore, EGFR phosphorylation can exert a key role in the production of superoxide anion and ROS induced by PN in MDA-MB-231 cells.

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Parthenolide: from plant shoots to cancer roots

Cited by 262 publications

References 75 publications

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

Parthenolide induces superoxide anion production by stimulating EGF receptor in MDA-MB-231 breast cancer cells

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