Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer

Curry, Eardie; Murry, Daryl J.; Yoder, C.; Fife, Karen; Armstrong, Victoria; Nakshatri, Harikrishna; O’Connell, Michael J.; Sweeney, Christopher J.

doi:10.1023/b:drug.0000026256.38560.be

Cited by 111 publications

(86 citation statements)

References 19 publications

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“…Reports of experiments that utilized a combination of PTL and radiation are few (37,38), while results of hyperthermia have only been presented in in vitro experiments (5). In addition, there is only a single report of PTL used for clinical cancer therapy in a phase I dose escalation trial (39).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of NF-κB by combination therapy with parthenolide and hyperthermia and kinetics of apoptosis induction and cell cycle arrest in human lung adenocarcinoma cells

Hayashi

Sakurai²,

Hayashi³

et al. 2009

Int J Mol Med

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Abstract. We investigated the mechanisms of thermosensitization related to combination therapy with sesquiterpene lactone parthenolide (PTL), a nuclear factor-κB (NF-κB) inhibitor, and hyperthermia using human lung adenocarcinoma cells A549. The kinetics of apoptosis induction and cell cycle of cells treated with PTL, heating, and combined treatment were examined by flow cytometric analysis. The flow cytometric distribution was calculated and expressed as a percentage. The ratios of the sub-G 1 division, used to determine the induction of apoptosis, increased significantly with the combination therapy. Furthermore, the ratios of G 2 /M division increased and the ratios of G 0 /G 1 division decreased, indicating cell cycle arrest in G 2 /M. The cell phase response to PTL by A549 cells synchronized in the G 1 /S border with hydroxyurea was also analyzed. PTL showed remarkable cytotoxicity at the S phase of the cell cycle in A549 cells at all concentrations as well as with hyperthermia, thus PTL reduced the number of cells in the proliferation phase. Inhibition of intracellular transcription factor NF-κB activation in A549 cells with various incubation periods after treatments with PTL, heating and combined treatment was examined by Western blot analysis. Unexpectedly, PTL alone did not inhibit NF-κB activation in cells stimulated with TNF-·, while heating alone inhibited NF-κB early after treatment and that effect faded over time. In contrast, PTL combined with heating completely inhibited NF-κB activation. Our results demonstrated that PTL and heating in combination cause significant thermosensitization of A549 cells via induction of apoptosis or cell cycle arrest in G 2 /M by inhibiting NF-κB activation in a synergistic manner.

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Section: Discussionmentioning

confidence: 99%

Inhibition of NF-κB by combination therapy with parthenolide and hyperthermia and kinetics of apoptosis induction and cell cycle arrest in human lung adenocarcinoma cells

Hayashi

Sakurai²,

Hayashi³

et al. 2009

Int J Mol Med

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“…Parthenolide, a sesquiterpene lactone that was first isolated from the feverfew herb (Tanacetum parthenium) is a relatively specific small molecule inhibitor of NF-kB (Bork et al, 1997;Hehner et al, 1999). Parthenolide has undergone a phase I clinical trial as an anticancer agent (Curry et al, 2004). Thus, combining clinically applicable HDACIs such as Depsipetide, MS-275 or SAHA with NF-kB inhibitor like Parthenolide to enhance the anticancer effect of HDACIs may have clinically translatable potential.…”

Section: Discussionmentioning

confidence: 99%

“…This was positively correlated with the more pronounced induction of apoptosis by the STP þ VA (1.0 mM) combination (Figure 8). We next investigated the effect of direct inhibition of NF-kB by using the pharmacologic inhibitor Parthenolide that interferes with NF-kB activation by targeting the IkB kinase complex via inhibition of NIK-and MEKK1-induced activation of IKKa and IKKb (Murphy et al, 1988;Bork et al, 1997;Hehner et al, 1999;Curry et al, 2004). Parthenolide at 30 mM completely abrogated VA-induced NF-kB transcriptional activation in the representative cultured thoracic cancer cells (Figure 4).…”

Section: Profound Enhancement Of Apoptosis Induction By Combining Va mentioning

confidence: 99%

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

et al. 2006

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Histone deacetylase inhibitors (HDACIs) are novel anticancer agents with potent cytotoxicity against a wide range of malignancies. We have previously demonstrated that either Calphostin C (CC) (a protein kinase C (PKC) inhibitor) or Parthenolide (an NF-kB inhibitor) abrogates HDACI-induced transcriptional activation of NF-kB and p21, which is associated with profound potentiation of HDACI-mediated induction of apoptosis. Valproic acid (VA), a commonly used antiepileptic agent, has recently been shown to be an HDACI. This study was aimed to evaluate the anticancer property of VA in thoracic cancer cells and the development of clinically relevant strategies to enhance VA-mediated induction of apoptosis using kinase inhibitors Staurosporine (STP) or its analogue UCN-01. Treating cultured thoracic cancer cells with VA (0.62 -10.0 mM) resulted in significant cell line-and dose-dependent growth inhibition (IC 50 values: 4.1 -6.0 mM) and cell cycle arrest at G1/S checkpoint with profound accumulation of cells at G0/G1 phase but little induction of apoptosis. Valproic acid, being an HDACI, caused significant dose-dependent accumulation of hyperacetylated histones, following 24 h of treatment. Valproic acid-mediated 5 -20-fold upregulation of transcriptional activity of NF-kB was substantially (50 -90%) suppressed by cotreatment with CC, STP or UCN-01. Whereas minimal death (o20%) was observed in cells treated with either VA (1.0 or 5.0 mM) alone or kinase inhibitors alone, 60 -90% of cells underwent apoptosis following exposure to combinations of VA þ kinase inhibitors. Kinase inhibitor-mediated suppression of NF-kB transcriptional activity played an important role in sensitising cancer cells to VA as direct inhibition of NF-kB by Parthenolide drastically synergised with VA to induce apoptosis (VA þ Parthenolide: 60 -90% compared to o20% following single-drug treatments). In conclusion, VA, a well-known antiepileptic drug, has mild growth-inhibitory activity on cultured cancer cells. The weak VA-mediated induction of apoptosis of thoracic cancer cells can be profoundly enhanced either by Parthenolide, a pharmacologic inhibitor of NF-kB, or by UCN-01 a kinase inhibitor that has already undergone phase I clinical development. Combinations of VA with either a PKC inhibitor or an NF-kB inhibitor are promising novel molecularly targeted therapeutics for thoracic cancers.

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“…Of note, there are also several natural products and natural product derivatives that can simultaneously inhibit both IKK and NF-kB DNA binding by affecting reactive Cys residues in their targets (Liang et al 99 and references therein) and such dual-specific inhibitors may have clinical relevance. 100 The IKK-independent signaling pathways that directly modify the NF-kB subunits themselves represent another potential drug discovery route. Inhibition or activation of such kinases would provide a route to modulate NF-kB directly, without totally inhibiting its function.…”

Section: Clinical Implications Of Nf-jb-mediated Tumor Suppressionmentioning

confidence: 99%

Good cop, bad cop: the different faces of NF-κB

2006

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Complexes formed from the nuclear factor jB (NF-jB) family of transcription factors are ubiquitously expressed and are induced by a diverse array of stimuli. This results in their becoming activated in a wide variety of different settings. While the functions of NF-jB in many of these contexts have been the subject of intense research and are now well established, it is also clear that there is great diversity in the effects and consequences of NF-jB activation. NF-jB subunits do not necessarily regulate the same genes, in an identical manner, in all of the different circumstances in which they are induced. This review will discuss the different functions of NF-jB, the pathways that modulate NF-jB subunit activity and, in contrast to its more commonly thought of role as a promoter of cancer cell growth and survival, the ability of NF-jB, under some circumstances, to behave as a tumor suppressor.

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Phase I dose escalation trial of feverfew with standardized doses of parthenolide in patients with cancer

Abstract: Feverfew, with up to 4 mg of parthenolide, given daily as an oral tablet is well tolerated without dose-limiting toxicity, but does not provide detectable plasma concentrations. Purification of parthenolide for administration of higher doses will be needed.

Cited by 111 publications

References 19 publications

Inhibition of NF-κB by combination therapy with parthenolide and hyperthermia and kinetics of apoptosis induction and cell cycle arrest in human lung adenocarcinoma cells

Inhibition of NF-κB by combination therapy with parthenolide and hyperthermia and kinetics of apoptosis induction and cell cycle arrest in human lung adenocarcinoma cells

Potentiation of the anticancer effect of valproic acid, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor Staurosporine or its clinically relevant analogue UCN-01

Good cop, bad cop: the different faces of NF-κB

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