Perillyl Alcohol Inhibits a Calcium-Dependent Constitutive Nuclear Factor-κB Pathway

Berchtold, Craig M.; Chen, Kai-Shun; Miyamoto, Shigeki; Gould, Michael N.

doi:10.1158/0008-5472.can-04-4072

Cited by 53 publications

(40 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This drug has been reported to inhibit cancer cell growth and to enhance the pro-apoptotic effects of combined chemotherapeutic drugs such as bortezomib or cisplatin in several malignant tumors including MCL. 13,25,26 We have shown herein POH (1mM), or the combination of bortezomib (100nM) and POH (1mM) for 16 hours. Nuclear extracts from untreated, bortezomib-treated, POH-treated, and combination-treated CD45 ϩ CD19 Ϫ MCL-ICs were analyzed using ELISA assays to assess p50 and p65 DNA-binding activities.…”

Section: Discussionmentioning

confidence: 83%

“…13,25,26 TG2 is a calcium-dependent cross-linking enzyme and, in addition to calcium, catalyzes the polymerization of IB␣. 37,38 We hypothesized that calcium blockers inhibit NF-B activation by inhibiting TG2 function.…”

Section: Calcium Blockers Inhibit Nf-b Activation and Tg2 Activity Inmentioning

confidence: 99%

“…13,25,26 Another study indicated that the L-type calcium-channel blocker verapamil enhanced the cytotoxic effects of bortezomib. 27 Therefore, in the present study, we investigated whether combination treatment with bortezomib plus calcium-channel blockers such as POH decreases the bortezomibresistant properties of MCL-ICs.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma via manipulation of tissue transglutaminase activities

Jung

Chen

Wang

et al. 2012

Blood

View full text Add to dashboard Cite

IntroductionMantle cell lymphoma (MCL) is an aggressive subtype of B-cell lymphoma that accounts for 5%-7% of cases of non-Hodgkin lymphoma. Despite good responses with first-line treatments for newly diagnosed, untreated MCL patients, 1-3 MCL patients often relapse and demonstrate highly refractory responses to common antilymphoma chemotherapy, which results in inevitable chemoresistance and poor clinical outcomes. [4][5][6][7] Bortezomib (Velcade), a reversible inhibitor of the 26S proteasome, first gained United States Food and Drug Administration approval as a single-agent treatment in patients with relapsed or refractory MCL. 8 Bortezomib inhibits the ubiquitin-proteasome pathway and alters multiple cellular signaling cascades, including those regulating cell growth, differentiation, and survival. [9][10][11] For example, proteasome inhibition prevents the degradation of proapoptotic factors, which facilitates the activation of programmed cell death in neoplastic cells; however, the precise mechanisms of action are controversial.One of the known bortezomib targets for inhibition is NF-B and its related pathway. Constitutive NF-B expression has been reported in MCL cell lines and primary cells. 12 However, therapies such as bortezomib targeting NF-B have shown limited effects in MCL. [13][14][15] Bortezomib was also reported to elicit the unfolded protein response, which is activated when the physiologic environment of the endoplasmic reticulum is altered. [16][17][18] The induction of endoplasmic reticulum stress induces reactive oxygen species, which affects treatment responses to bortezomib in MCL 18 and multiple myeloma. 19 In addition, some studies have suggested that bortezomib could increase NF-B activity 20,21 or the presence of bortezomib-resistant NF-B activity in MCL. 13 The resistance to drugs such as bortezomib in MCL suggest the presence of drug-resistant populations in MCL. In a previous study, we prospectively identified stem-like cells in MCL, which we have termed MCL-initiating cells (MCL-ICs). 22 The stem-like MCL cells (CD45 ϩ CD19 Ϫ CD34 Ϫ CD3 Ϫ ) were highly tumorigenic and display self-renewal capacities in NOD/SCID mice. In contrast, the majority of the tumor population contains CD45 ϩ CD19 ϩ MCL cells, which show no self-renewal capacity and have greatly reduced tumorigenicity. 22 We also demonstrated that these CD45 ϩ CD19 Ϫ MCL-ICs confer drug resistance properties to MCL. MCL-ICs were highly resistant in vitro to clinically relevant anti-MCL chemotherapeutic regimens compared with bulk CD45 ϩ CD19 ϩ MCL cells. 23 Moreover, CD45 ϩ CD19 Ϫ MCL-ICs were resistant to bortezomib and bortezomib-based chemotherapeutic regimens despite constitutive NF-B expression. 24 Bortezomibbased regimens targeted CD45 ϩ CD19 Ϫ MCL-ICs less efficiently compared with CD45 ϩ CD19 ϩ bulk MCL cells. Based on these findings, a new strategy is required to overcome bortezomib resistance in MCL.Recent studies have demonstrated that perillyl alcohol (POH), a naturally occurring monoterpene that inhibits L-type ...

show abstract

Section: Discussionmentioning

confidence: 83%

Section: Calcium Blockers Inhibit Nf-b Activation and Tg2 Activity Inmentioning

confidence: 99%

See 1 more Smart Citation

Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma via manipulation of tissue transglutaminase activities

Jung

Chen

Wang

et al. 2012

Blood

View full text Add to dashboard Cite

show abstract

“…Several isolated substances of aromatic plants demonstrated remarkable pharmacological actions through inhibition of NF-kB activity, as 4-nerolydilcathecol. Previous studies have shown that limonene, perillyl alcohol and menthol inhibited the activation of NF-қB (Berchtold et al, 2005;Salminen et al, 2008). α-Pinene, which is also a monoterpene, revealed a robust activity by inhibiting translocation of NF-қB to the cell nucleus, increasing the expression of the inhibitory protein IқB (Zhou et al, 2004).…”

Section: In Vitro Inhibition Of Nuclear Factor Kappa Bmentioning

confidence: 99%

Investigation of the inhibitory effects from the Brazilian medicinal plant Pothomorphe umbellata L. (Piperaceae) on the molecular pathways of cyclooxygenase-2 and nuclear factor kappa B

Lopes¹,

Bagatela²,

Fonseca³

et al. 2016

J. Med. Plants Res.

View full text Add to dashboard Cite

Presently, medicinal plants, such as Pothomorphe umbellata L. (Piperaceae), have been assessed as sources of potential therapeutic medicines. The inhibitory effects of the crude extract, fractions and 4-nerolidylcathecol, a phenolic compound which has been assigned significant activity in several beneficial properties performed by the plant, on the molecular pathways of cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB) were evaluated. The in vitro inhibition of COX-2 was performed by enzyme-linked immunosorbent assay (ELISA). Methylene chloride fraction demonstrated the preeminent inhibition of COX-2. In order to estimate the inhibition of NF-κB, an adaptation of the luciferase plasmid assay was developed. 4-Nerolidylcathecol presented the best inhibition NF-κB activity. The results obtained from the in vitro assays were promising, mainly on the molecular pathway of NF-κB, once 4-nerolidylcathecol demonstrated a remarkable inhibition activity.

show abstract

“…This therapeutic phase I trial showed limited promising results (Ripple et al 2000). We later discovered that POH inhibited the antiapoptotic ability of cancers via a calcium channel interaction that led to the downregulation of NFkB (Berchtold et al 2005). This mechanism of action could underlie the cytostatic and cytotoxic actions of POH toward both premalignant and malignant cells.…”

mentioning

confidence: 99%

The Utility of Comparative Genetics to Inform Breast Cancer Prevention Strategies

Gould

2009

Genetics

View full text Add to dashboard Cite

My research seeks to aid in developing approaches to prevent breast cancer. This research evolved from our early empirical studies for discovering natural compounds with anticancer activities, coupled with clinical evaluation to a genetics-driven approach to prevention. This centers on the use of comparative genomics to discover risk-modifying alleles that could help define population and individual risk and also serve as potential prevention drugable targets to mitigate risk. Here, we initially fine map mammary cancer loci in a rat carcinogenesis model and then evaluate their human homologs in breast cancer case-control association studies. This approach has yielded promising results, including the finding that the compound rat QTL Mcs5a's human homologous region was associated with breast cancer risk. These and related findings have the potential to yield advancements both in translation-prevention research and in basic molecular genetics. W RITING this Perspectives for Genetics allows meto examine how a cancer biologist focused on cancer prevention morphed into a practicing geneticist. In addition, it allows me to review a decade of our investigations into the complexity of the genetic risk to breast cancer development using comparative genomics.Our comparative genomic strategy consists of genetically identifying mammary cancer risk loci using fine mapping studies in a rat mammary carcinogenesis model. Human homologs of these loci are then evaluated in human breast cancer association studies for their potential to modify risk. This genetics approach provides an integrated discovery platform to identify and mechanistically characterize novel breast cancer risk alleles. We predict that this platform will serve as a foundation for a cancer prevention drug development pipeline.My early work focused on the etiology and prevention of breast cancer. It is work on these interrelated areas that led me to investigate breast cancer genetics. While studying the etiology of breast cancer after joining the faculty of the University of Wisconsin, my interest targeted early events in the etiology of cancer. These range from altering the metabolic activation of environmental xenobiotics to metabolites capable of adducting DNA to destroying clones premalignant cells. At the time we began work in this area, cancer chemoprevention was an emerging field that was assumed to be less complex than cancer therapy. This was, in part, based on the fact that normal and premalignant tissues were genetically more stable than cancer cells and thus less likely to develop resistance to anticancer drugs.Our chemoprevention studies focused on a novel class of nontoxic monoterpenes widely found in the essential oils of fruits. These compounds were found to have both preventive and therapeutic anticancer activities in being able to inhibit both premalignant and malignant cells. Our lead compound was limonene, found in orange peel oil, and the first monoterpene we entered into FDAapproved clinical trials was perillyl alcohol (POH), found o...

show abstract

Perillyl Alcohol Inhibits a Calcium-Dependent Constitutive Nuclear Factor-κB Pathway

Cited by 53 publications

References 46 publications

Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma via manipulation of tissue transglutaminase activities

Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma via manipulation of tissue transglutaminase activities

Investigation of the inhibitory effects from the Brazilian medicinal plant Pothomorphe umbellata L. (Piperaceae) on the molecular pathways of cyclooxygenase-2 and nuclear factor kappa B

The Utility of Comparative Genetics to Inform Breast Cancer Prevention Strategies

Contact Info

Product

Resources

About