Susan Lehman Cullman Laboratory for Cancer Research

Piscataway, NJ, United States

Susan Lehman Cullman Laboratory for Cancer Research

Piscataway, NJ, United States
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Zhou D.-Y.,Guangdong University of Technology | Zhou D.-Y.,Guangdong Food and Drug Vocational College | Zhang K.,Guangdong University of Technology | Conney A.H.,Guangdong University of Technology | And 10 more authors.
Chemical and Pharmaceutical Bulletin | Year: 2013

Eleven curcumin-related compounds containing a benzyl piperidone moiety were synthesized and evaluated for their effects on cultured prostate cancer PC-3 cells, pancreas cancer BxPC-3 cells, colon cancer HT-29 cells and lung cancer H1299 cells. Inhibitory effects of these compounds on the growth of PC-3, BxPC-3, HT-29 and H1299 cells were determined by the 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue exclusion assay. Compounds benzyl piperidone 2 (P2), P4, P7, 4-bromo-2-fluoro-benzyl piperidone 2 (PFBr2), PFBr3 and PFBr4 (see syntheses and structures in Figs. 1, 2) exhibited potent inhibitory effects on the growth of cultured PC-3, BxPC-3, HT-29 and H1299 cells. The IC50 for these compounds was lower than 2 μM in all four cell lines. PFBr4 was 41-, 36-, 40- and 46-fold more active than curcumin for inhibiting the growth of PC-3, BxPC-3, HT-29 and H1299 cells, respectively. The benzyl piperidone-containing compounds studied also stimulated apoptosis in PC-3 cells. Mechanistic studies indicate that the effects of both curcumin and PFBr4 on PC-3 cells were associated with a decrease in phospho-Akt and phospho-extracellular signal-regulated kinase (Erk)1/2. The present study indicates that P2, P4, P7, PFBr2, PFBr3 and PFBr4 may have useful effects on human cancer cells. © 2013 The Pharmaceutical Society of Japan.


Wei X.,Guangzhou University | Zhou D.,Guangdong University of Technology | Wang H.,Guangdong University of Technology | Ding N.,Susan Lehman Cullman Laboratory for Cancer Research | And 10 more authors.
Anticancer Research | Year: 2013

Twelve pyridine analogs of curcumin were studied for their effects on growth and apoptosis in human prostate cancer PC-3 cells. The ability of these compounds to inhibit the transcriptional activity of nuclear factor-kappa B (NF-κB) and the level of phosphorylated extracellular signal-regulated kinases (phospho-ERK1/2) in PC-3 cells was also determined. Treatment of PC-3 cells with the pyridine analogs of curcumin resulted in concentration-dependent growth inhibition and apoptosis stimulation. Only pyridine analogs of curcumin with a tetrahydrothiopyrane-4-one linker (FN compounds) exhibited a strong inhibitory effect on growth and a strong stimulatory effect on apoptosis at low concentrations (≤1 μM). Mechanistic studies showed that NF-κB transcriptional activity in PC-3 cells was strongly inhibited by treatment with group FN compounds. Treatment of PC-3 cells with 1 μM FN1 resulted in a decrease of activated ERK1/2. Results from the present study indicate that FN compounds warrant further in vivo studies using suitable animal models of prostate cancer.


Lee H.J.,Sookmyung Womens University | Lee H.J.,Susan Lehman Cullman Laboratory for Cancer Research | Wall B.A.,Susan Lehman Cullman Laboratory for Cancer Research | Wall B.A.,Rutgers University | And 10 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Melanoma is a heterogeneous disease where monotherapies are likely to fail due to variations in genomic signatures. B-RAF inhibitors have been clinically inadequate but response might be augmented with combination therapies targeting multiple signaling pathways. We investigate the preclinical efficacy of combining the multikinase inhibitor sorafenib or the mutated B-RAF inhibitor PLX4720 with riluzole, an inhibitor of glutamate release that antagonizes metabotropic glutamate receptor 1 (GRM1) signaling in melanoma cells. Experimental Design: Melanoma cell lines that express GRM1 and either wild-type B-RAF or mutated B-RAF were treated with riluzole, sorafenib, PLX4720, or the combination of riluzole either with sorafenib or with PLX4720. Extracellular glutamate levels were determined by glutamate release assays. MTT assays and cell-cycle analysis show effects of the compounds on proliferation, viability, and cell-cycle profiles. Western immunoblotting and immunohistochemical staining showed apoptotic markers. Consequences on mitogen-activated protein kinase pathway were assessed by Western immunoblotting. Xenograft tumor models were used to determine the efficacy of the compounds in vivo. Results: The combination of riluzole with sorafenib exhibited enhanced antitumor activities in GRM1-expressing melanoma cells harboring either wild-type or mutated B-RAF. The combination of riluzole with PLX4720 showed lessened efficacy compared with the combination of riluzole and sorafenib in suppressing the growth of GRM1-expressing cells harboring the B-RAF V600E mutation. Conclusions: The combination of riluzole with sorafenib seems potent in suppressing tumor proliferation in vitro and in vivo in GRM1-expressing melanoma cells regardless of B-RAF genotype and may be a viable therapeutic clinical combination. ©2011 AACR.


Lou Y.-R.,Susan Lehman Cullman Laboratory for Cancer Research | Peng Q.Y.,Susan Lehman Cullman Laboratory for Cancer Research | Li T.,Susan Lehman Cullman Laboratory for Cancer Research | Medvecky C.M.,Rutgers University | And 8 more authors.
Carcinogenesis | Year: 2011

Our previous studies reported that caffeine or voluntary exercise decreased skin tumor multiplicity, in part, by decreasing fat levels in the dermis. These data suggest that tissue fat may play an important role in regulating ultraviolet light (UV) B-induced skin tumor development. In the present study, we explored the effects of high-fat diets rich in either omega-3 or omega-6 fatty acids on UVB-induced skin carcinogenesis. SKH-1 mice were irradiated with 30 mJ/cm2 of UVB once a day, two times per week for 39 weeks. During UVB treatment, one group of mice was given a high-fat fish oil (HFFO) diet rich in omega-3 fatty acids and the other group of mice was given a high-fat mixed-lipids (HFMLs) diet rich in omega-6 fatty acids. The results showed that, compared with HFML diet, HFFO treatment (i) increased latency for the development of UVB-induced skin tumors; (ii) decreased the formation of papilloma, keratoacanthoma and carcinoma by 64, 52 and 46%, respectively and (iii) decreased the size of papilloma, keratoacanthoma and carcinoma by 98, 80 and 83%, respectively. Mechanistic studies with antibody array revealed that compared with HFML diet, administration of HFFO to the mice significantly decreased the UVB-induced increases in the levels of TIMP-1, LIX and sTNF R1 as well as other several proinflammatory cytokines and stimulated the UVB-induced apoptosis in the epidermis. Our results indicate that omega-3 fatty acids in HFFO diet have beneficial effects against UVB-induced skin carcinogenesis, and these effects may be associated with an inhibition on UVB-induced inflammatory response. © The Author 2011. Published by Oxford University Press. All rights reserved.


Khor T.O.,Rutgers University | Fuentes F.,Rutgers University | Shu L.,Rutgers University | Paredes-Gonzalez X.,Rutgers University | And 6 more authors.
Chest | Year: 2014

Epigenetic control of NRF2, a master regulator of many critical antioxidative stress defense genes in human prostate cancer (CaP), is unknown. Our previous animal study found decreased Nrf2 expression through promoter CpG methylation/histone modifications during prostate cancer progression in TRAMP mice. In this study, we evaluated CpG methylation of human NRF2 promoter in 27 clinical prostate cancer samples and in LNCaP cells using MAQMA analysis and bisulfite genomic DNA sequencing. Prostate cancer tissue microarray (TMA) containing normal and prostate cancer tissues was studied by immunohistochemistry. Luciferase reporter assay using specific human NRF2 DNA promoter segments and chromatin immunoprecipitation (ChIP) assay against histone modifying proteins were performed in LNCaP cells. Three specific CpG sites in the NRF2 promoter were found to be hypermethylated in clinical prostate cancer samples (BPH


Martino J.J.,Susan Lehman Cullman Laboratory for Cancer Research | Wall B.A.,Susan Lehman Cullman Laboratory for Cancer Research | Mastrantoni E.,Susan Lehman Cullman Laboratory for Cancer Research | Mastrantoni E.,University of Rome Sapienze | And 7 more authors.
Oncogene | Year: 2013

Non-neuronal expression of components of the glutamatergic system has been increasingly observed, and our laboratory previously had demonstrated the etiological role of ectopically expressed metabotropic glutamate receptor 1 (Grm1/mGluR1) in mouse models of melanoma. We hypothesize that inappropriate glutamatergic signaling in other cell types can dysregulate growth leading to transformation and tumorigenesis. As most cancers are carcinomas, we selected an immortalized primary baby mouse kidney (iBMK) cell model to assess whether Grm1 can transform epithelial cells. These iBMK cells, engineered to be immortal yet nontumorigenic and retaining normal epithelial characteristics, were used as recipients for exogenous Grm1 cDNA. Several stable Grm1-expressing clones were isolated and the Grm1-receptors were shown to be functional, as evidenced by the accumulation of second messengers in response to Grm1 agonist. Additionally activated by agonist were mitogen-activated protein kinase (MAPK) and AKT/protein kinase B signaling cascades, the major intracellular pathways shown by many investigators to be critical in melanomagenesis and other neoplasms. These Grm1-iBMK cells exhibited enhanced cell proliferation in in vitro methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays and significant tumorigenicity in in vivo allografts. Persistent Grm1 expression was required for the maintenance of the in vivo tumorigenic phenotype as demonstrated by an inducible Grm1-silencing RNA. These are the first results that indicate that Grm1 can be an oncogene in epithelial cells. In addition, relevance to human disease in the corresponding tumor type of renal cell carcinoma (RCC) may be suggested by observed expression of GRM1/mGluR1 in a number of RCC tumor biopsy samples and cell lines, and the effects of GRM1 modulation on tumorigenicity therein. Moreover, RCC cell lines exhibited elevated levels of extracellular glutamate, and some lines responded to drugs, which modulate the glutamatergic system. These findings imply a possible role for glutamate signaling apparatus in RCC cell growth, and that the glutamatergic system may be a therapeutic target in RCC. & 2013 Macmillan Publishers Limited. © 2013 Macmillan Publishers Limited.


Yue W.,Albany State University | Yang C.S.,Albany State University | Yang C.S.,Susan Lehman Cullman Laboratory for Cancer Research | DiPaola R.S.,Albany State University | And 2 more authors.
Cancer Prevention Research | Year: 2014

Pancreatic cancer, as the fourth leading cause of cancer-related deaths, carries a poor prognosis with a median survival of 6 months and a dismal 5-year survival rate of 3% to 5%. These statistics highlight an urgent need for novel chemopreventive and therapeutic strategies for this malignancy. Metformin and aspirin have been explored as two emerging cancer chemoprevention agents for different types of cancers, including pancreatic cancer. Here, we review the effects of both metformin and aspirin on pancreatic tumorigenesis and their potential actions in pancreatic cancer. Special attention is paid to their effects on the important signaling pathways of pancreatic cancer development as well as possible mechanisms for synergy between these two agents. For metformin, the most important mechanism may involve the inhibition of mTOR signaling via AMP-activated protein kinase (AMPK)-dependent and -independent pathways. For aspirin, the major mechanism is the anti-inflammatory action through the inhibition of COX-1/COX-2 and modulation of the NFκB or STAT3 pathway. In addition, aspirin may activate AMPK, and both agents may affect Notch, Wnt/β-catenin, and other signaling pathways. The combination of metformin and aspirin will provide additive and possibly synergistic effects for the prevention and treatment of pancreatic cancer. ©2014 AACR.


Yang Z.,Susan Lehman Cullman Laboratory for Cancer Research | Lee M.-J.,Susan Lehman Cullman Laboratory for Cancer Research | Zhao Y.,Susan Lehman Cullman Laboratory for Cancer Research | Yang C.S.,Susan Lehman Cullman Laboratory for Cancer Research | Yang C.S.,Cancer Institute of New Jersey
Genes and Nutrition | Year: 2012

Tocotrienols (T3s), members of the vitamin E family, exhibit potent anti-cancer, anti-oxidative, antiinflammatory, and some other biological activities. To better understand the bioavailability and metabolism of T3s, T3s and their metabolites were identified in urine and fecal samples from mice on diet supplemented with mixed T3s using HPLC/electrochemical detection and liquid chromatography electrospray ionisation mass spectrometry (LC-ESI-MS). Whereas the short-chain metabolites carboxyethyl hydroxychromans (CEHCs) and carboxymethylbutyl hydroxychromans (CMBHCs) were the major metabolites of T3s, several new metabolites with double bonds were also identified. Similar to tocopherols, the majority of T3 metabolites were excreted as sulfate/ glucuronide conjugates in mouse urine. The distribution of γ- and δ-T3 and γ-T3 metabolites were also determined in different organs as well as in urine and fecal samples from mice on diets supplemented with corresponding T3s. The synergistic anti-cancer actions of γ-T3 and atorvastatin (ATST) were studied in HT29 and HCT116 colon cancer cell lines. The combination greatly potentiated the ability of each individual agent to inhibit cancer cell growth and to induce cell cycle arrest and apoptosis. The triple combination of γ-T3, ATST, and celecoxib exhibited synergistic actions when compared with any double combination plus the third agent. Mechanistic studies revealed that the synergistic actions of γ-T3 and ATST could be attributed to their mediation of 3-hydroxy-3-methyl-glutaryl-CoA reductase, and the subsequent inhibition of protein geranylgeranylation. It remains to be determined whether such a synergy occurs in vivo. © Springer-Verlag 2011.


Bernard J.J.,University of California at San Diego | Bernard J.J.,Susan Lehman Cullman Laboratory for Cancer Research | Cowing-Zitron C.,University of California at San Diego | Nakatsuji T.,University of California at San Diego | And 9 more authors.
Nature Medicine | Year: 2012

Exposure to ultraviolet B (UVB) radiation from the sun can result in sunburn, premature aging and carcinogenesis, but the mechanism responsible for acute inflammation of the skin is not well understood. Here we show that RNA is released from keratinocytes after UVB exposure and that this stimulates production of the inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) from nonirradiated keratinocytes and peripheral blood mononuclear cells (PBMCs). Whole-transcriptome sequencing revealed that UVB irradiation of keratinocytes induced alterations in the double-stranded domains of some noncoding RNAs. We found that this UVB-damaged RNA was sufficient to induce cytokine production from nonirradiated cells, as UVB irradiation of a purified noncoding RNA (U1 RNA) reproduced the same response as the one we observed to UVB-damaged keratinocytes. The responses to both UVB-damaged self-RNAs and UVB-damaged keratinocytes were dependent on Toll-like receptor 3 (TLR3) and Toll-like receptor adaptor molecule 1 (TRIF). In response to UVB exposure, Tlr3-/- mice did not upregulate TNF-α in the skin. Moreover, TLR3 was also necessary for UVB-radiation-induced immune suppression. These findings establish that UVB damage is detected by TLR3 and that self-RNA is a damage-Associated molecular pattern that serves as an endogenous signal of solar injury. © 2012 Nature America, Inc. All rights reserved.


Bernard J.J.,Susan Lehman Cullman Laboratory for Cancer Research | Lou Y.-R.,Susan Lehman Cullman Laboratory for Cancer Research | Peng Q.-Y.,Susan Lehman Cullman Laboratory for Cancer Research | Li T.,Susan Lehman Cullman Laboratory for Cancer Research | Lu Y.-P.,Susan Lehman Cullman Laboratory for Cancer Research
PLoS ONE | Year: 2014

Our previous studies demonstrated that the topical application of caffeine is a potent inhibitor of UVB-induced carcinogenesis and selectively increases apoptosis in tumors but not in non-tumor areas of the epidermis in mice that are at a high risk for developing skin cancer. While this effect is mainly through a p53 independent pathway, the mechanism by which caffeine inhibits skin tumor formation has not been fully elucidated. Since caffeine is a non-specific phosphodiesterase inhibitor, we investigated the effects of several PDE inhibitors on the formation of sunburn cells in mouse skin after an acute exposure to ultraviolet light B (UVB). The topical application of a PDE2 inhibitor, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA hydrochloride), stimulated epidermal apoptosis compared to control (P<0.01) and to a greater extent than caffeine whereas a PDE4 inhibitor attenuated the epidermal apoptosis compared to control (P<0.01). Since PDE2 hydrolyzes cyclic nucleotides, mainly cGMP, the effects of EHNA hydrochloride on epidermal apoptosis following UVB exposure may be mediated, in part, by increased cGMP signaling. Data demonstrated that the topical application of dibutyryl cGMP stimulated epidermal apoptosis (P<0.01) following an acute exposure to UVB. Treating UVB-pretreated mice topically with 3.1 μmole or 0.8 mmole of EHNA hydrochloride attenuated tumor formation to a greater extent than treating with 6.2 m mole caffeine when these compounds were applied once a day, five days a week for 18 weeks. These observations suggest a novel role for PDE2 in UVB-induced tumorigenesis and that PDE2 inhibitors that mediate cGMP signaling may be useful for the prevention and treatment of skin cancer. © 2014 Bernard et al.

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