Publications by authors named "Debra L Bemis"

12 Publications

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Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells.

Elife 2015 Aug 18;4. Epub 2015 Aug 18.

Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, United States.

Resistance to targeted cancer therapies is an important clinical problem. The discovery of anti-resistance drug combinations is challenging as resistance can arise by diverse escape mechanisms. To address this challenge, we improved and applied the experimental-computational perturbation biology method. Using statistical inference, we build network models from high-throughput measurements of molecular and phenotypic responses to combinatorial targeted perturbations. The models are computationally executed to predict the effects of thousands of untested perturbations. In RAF-inhibitor resistant melanoma cells, we measured 143 proteomic/phenotypic entities under 89 perturbation conditions and predicted c-Myc as an effective therapeutic co-target with BRAF or MEK. Experiments using the BET bromodomain inhibitor JQ1 affecting the level of c-Myc protein and protein kinase inhibitors targeting the ERK pathway confirmed the prediction. In conclusion, we propose an anti-cancer strategy of co-targeting a specific upstream alteration and a general downstream point of vulnerability to prevent or overcome resistance to targeted drugs.
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http://dx.doi.org/10.7554/eLife.04640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539601PMC
August 2015

beta-carboline alkaloid-enriched extract from the amazonian rain forest tree pao pereira suppresses prostate cancer cells.

J Soc Integr Oncol 2009 ;7(2):59-65

Department of Urology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.

Bark extracts from the Amazonian rain forest tree Geissospermum vellosii (pao pereira), enriched in alpha-carboline alkaloids have significant anticancer activities in certain preclinical models. Because of the predominance of prostate cancer as a cause of cancer-related morbidity and mortality for men of Western countries, we preclinically tested the in vitro and in vivo effects of a pao pereira extract against a prototypical human prostate cancer cell line, LNCaP. When added to cultured LNCaP cells, pao pereira extract significantly suppressed cell growth in a dose-dependent fashion and induced apoptosis. Immunodeficient mice heterotopically xenografted with LNCaP cells were gavaged daily with pao pereira extract or vehicle control over 6 weeks. Tumor growth was suppressed by up to 80% in some groups compared with tumors in vehicle-treated mice. However, we observed a striking U-shaped dose-response curve in which the highest dose tested (50 mg/kg/d) was much less effective in inducing tumor cell apoptosis and in reducing tumor cell proliferation and xenograft growth compared with lower doses (10 or 20 mg/kg/d). Although this study supports the idea that a pao pereira bark extract has activity against human prostate cancer, our in vivo results suggest that its potential effectiveness in prostate cancer treatment may be limited to a narrow dose range.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358020PMC
June 2009

Dietary agents/supplements hit the clinic for prostate cancer chemoprevention.

Discov Med 2007 Feb;7(37):33-8

Department of Urology, Columbia University Medical Center, New York, NY 10032, USA.

Dietary studies of men throughout the world have identified certain foods/food-derived substances that are correlated to prostate cancer risk. While radical modification of cultural dietary habits with the goal of preventing prostate cancer remains challenging, supplementation with certain foods and/or food-derived substances identified as having potential chemopreventative properties may be a feasible approach, particularly for Western cultures. Before such chemopreventative strategies can be recommended to patients, their benefits must be rigorously demonstrated in appropriately designed clinical trials. This paper discusses several agents currently under scientific scrutiny for prostate cancer chemopreventative activities and the data available, thus far.
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February 2007

A pilot study on acupuncture for lower urinary tract symptoms related to chronic prostatitis/chronic pelvic pain.

Chin Med 2007 Feb 6;2. Epub 2007 Feb 6.

Department of Urology, Columbia University Medical Center, New York, NY 10032, USA.

Background: The etiology and treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) remain poorly understood. Pain, lower urinary tract voiding symptoms and negative impact on quality of life (QOL) are the most common complaints. Acupuncture, which has been widely used to treat painful and chronic conditions, may be a potential treatment to alleviate the constellation of symptoms experienced by men with CP/CPPS. The purpose of our study was to assess the impact of standardized full body and auricular acupuncture in men refractory to conventional therapies and collect pilot data to warrant further randomized trials.

Methods: Ten men diagnosed with category IIIA or IIIB CP/CPPS >6 months, refractory to at least 1 conventional therapy (antibiotics, anti-inflammatory agents, 5-alpha reductase inhibitors, alpha-1 blockers) and scoring >4 on the pain subset of the NIH-CPSI were prospectively analyzed in an Institutional Review Board (IRB) approved, single-center clinical trial (Columbia University Medical Center IRB#AAAA-7460). Standardized full body and auricular acupuncture treatment was given twice weekly for 6 weeks. The primary endpoints were total score of the NIH-CPSI and assessment of serious adverse events. The secondary endpoints were individual scores of the NIH-CPSI and QOL questionnaire scores of the short-form 36 (SF-36).

Results: The median age of the subjects was 36 years (range 29-63). Decreases in total NIH-CPSI scores (mean +/- SD) after 3 and 6 weeks from baseline (25.1 +/- 6.6) were 17.6 +/- 5.7 (P < 0.006) and 8.8 +/- 6.2 (P < 0.006) respectively and remained significant after an additional 6 weeks of follow-up (P < 0.006). Symptom and QOL/NIH-CPSI sub-scores were also significant (P < 0.002 and P < 0.002 respectively). Significance in 6 of 8 categories of the SF-36 including bodily pain (P < 0.002) was achieved. One regression in the SF-36 vitality category was observed after follow-up. There were no adverse events.

Conclusion: The preliminary findings, although limited, suggest the potential therapeutic role of acupuncture in the treatment of CP/CPPS. Data from this and previous studies warrant randomized trials of acupuncture for CP/CPPS and particular attention towards acupuncture point selection, treatment intervention, and durability of acupuncture.
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http://dx.doi.org/10.1186/1749-8546-2-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1800847PMC
February 2007

Clinical trials of natural products as chemopreventive agents for prostate cancer.

Expert Opin Investig Drugs 2006 Oct;15(10):1191-200

Columbia University Medical Center, Department of Urology, College of Physicians & Surgeons, Herbert Irving Pavilion, 11th Floor, 161 Fort Washington Avenue, New York, NY 10032, USA.

Epidemiological research on prostate cancer risk in men throughout the world has identified significant correlations between dietary habits and prostate cancer occurrence. These studies served as a catalyst for exploration into the potential of dietary substances to act as chemopreventive agents against this disease, and include green tea catechins, lycopene, soy isoflavones, pomegranate phenolics, selenium, vitamins E and D, curcumin and resveratrol. Before these agents (in the dietary or purified forms) can be recommended as useful chemopreventive strategies for patients, their activity must be confirmed in rigorously designed clinical trials. This review discusses the preclinical and clinical data available for these dietary agents and describes relevant clinical trials currently being conducted.
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http://dx.doi.org/10.1517/13543784.15.10.1191DOI Listing
October 2006

The use of herbal and over-the-counter dietary supplements for the prevention of prostate cancer.

Curr Urol Rep 2006 May;7(3):166-74

Department of Urology, Columbia University, 161 Fort Washington Avenue, New York, NY 10032, USA.

Having a high probability of experiencing prostate cancer during their lifetime, men are increasingly seeking protection against this disease with the use of over-the-counter dietary supplements containing herbs, vitamins, or plant-derived biochemical agents. The use of these agents for prostate cancer prevention is driven by epidemiology supporting the idea that regional diets and consumption of specific dietary components (certain herbs, vitamins, isoflavones, and polyphenols) are associated with a lower risk for prostate cancer, in conjunction with basic research that is defining molecules within food substances that kill or suppress growth of cultured human prostate cancer cells. Moreover, there is a sense that these dietary agents lack side effects, although this assumption often is faulty. Unfortunately, at this time, there is insufficient clinical evidence to support the widespread use of these dietary supplements for chemoprevention of prostate cancer, although ongoing clinical trials of the most promising vitamins and minerals are approaching conclusion.
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http://dx.doi.org/10.1007/s11934-006-0017-xDOI Listing
May 2006

The use of herbal and over-the-counter dietary supplements for the prevention of prostate cancer.

Curr Oncol Rep 2006 May;8(3):228-36

Department of Urology, Columbia University, Irving-11, 161 Fort Washington Avenue, New York, NY 10032, USA.

Having a high probability of experiencing prostate cancer during their lifetime, men are increasingly seeking protection against this disease with the use of over-the-counter dietary supplements containing herbs, vitamins, or plant-derived biochemical agents. The use of these agents for prostate cancer prevention is driven by epidemiology supporting the idea that regional diets and consumption of specific dietary components (certain herbs, vitamins, isoflavones, and polyphenols) are associated with a lower risk for prostate cancer, in conjunction with basic research that is defining molecules within food substances that kill or suppress growth of cultured human prostate cancer cells. Moreover, there is a sense that these dietary agents lack side effects, although this assumption often is faulty. Unfortunately, at this time, there is insufficient clinical evidence to support the widespread use of these dietary supplements for chemoprevention of prostate cancer, although ongoing clinical trials of the most promising vitamins and minerals are approaching conclusion.
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http://dx.doi.org/10.1007/s11912-006-0024-6DOI Listing
May 2006

Complementary and alternative medicine for chronic prostatitis/chronic pelvic pain syndrome.

Evid Based Complement Alternat Med 2005 Dec 10;2(4):495-501. Epub 2005 Oct 10.

Department of Urology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.

To discuss challenges concerning treatment for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and review complementary and alternative medical (CAM) therapies being evaluated for this condition, we performed a comprehensive search of articles published from 1990-2005 using the PubMed, Medline databases. Data from the articles were abstracted and pooled by subject. Keywords cross-searched with CP/CPPS included: complementary, alternative, integrative, therapies, interventions, nutrition, antioxidants, herbs, supplements, biofeedback and acupuncture. Listed articles with no abstracts were not included. Various CAM therapies for CP/CPPS exist including biofeedback, acupuncture, hyperthermia and electrostimulation. Additionally, a variety of in vitro and in vivo studies testing herbal and nutritional supplements were found. Saw palmetto, cernilton and quercetin were the most frequently tested supplements for CP/CPPS. Although many CAM therapies demonstrate positive preliminary observations as prospective treatments for CP/CPPS, further exploratory studies including more randomized, controlled trials are necessary for significant validation as treatment options for this complex disorder.
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http://dx.doi.org/10.1093/ecam/neh128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1297501PMC
December 2005

Zyflamend, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression.

Nutr Cancer 2005 ;52(2):202-12

Department of Urology, Columbia University Medical Center, New York, NY 10032, USA.

Cyclooxygenase (COX) inhibitors have suppressive effects on several types of cancer cells including prostate cancer. In this study, we considered the potential COX-inhibitory activity of a unique anti-inflammatory herbal preparation (Zyflamend; New Chapter, Inc., Brattleboro, VT) and analyzed its effects on the human prostate cancer cell line LNCaP. COX inhibitory activity of Zyflamend was determined by a spectrophotometric-based assay using purified ovine COX-1 and COX-2 enzymes. Effects of Zyflamend on LNCaP cell growth and apoptosis in vitro were assessed by cell counting, Western blot detection of poly ADP-ribose polymerase (PARP) cleavage, and measurement of caspase-3 activity in treated and control cell extracts. Western blotting techniques were conducted to determine the effects of this herbal preparation on the expression of the cell signaling proteins, p21, androgen receptor (AR), phospho-protein kinase C (pPKC)(alpha/beta), and phospho (p)Stat3. The phospohorylation status of several signal transduction phosphoproteins was profiled using a high-throughput phosphoprotein screening assay in treated cells and compared to controls. Zyflamend dramatically decreased COX-1 and COX-2 enzymatic activity. Elevated p21 expression coincided with attenuated cell growth following treatment of LNCaP cells with Zyflamend. PARP cleavage fragments were evident, and caspase-3 activity was upregulated over the control indicating the ability of Zyflamend to induce apoptosis of these cells. Androgen receptor expression levels declined by 40%, and decreases were observed in the active forms of Stat3 and PKC(alpha/beta) in Zyflamend-treated LNCaP cells. Zyflamend inhibited both COX-1 and COX-2 enzymatic activities, suppressed cell growth, and induced apoptosis in LNCaP cells. However, our data suggests that the effects are likely due to COX-independent mechanisms potentially involving enhanced expression of p21 and reduced expression of AR, pStat3, and pPKC(alpha/beta).
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http://dx.doi.org/10.1207/s15327914nc5202_10DOI Listing
January 2006

A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells.

Cancer Res 2005 Jun;65(12):5263-71

Department of Urology, First Hospital, Peking University, Beijing, China.

Protocadherin-PC (PCDH-PC) is a gene on the human Y chromosome that is selectively expressed in apoptosis- and hormone-resistant human prostate cancer cells. The protein encoded by PCDH-PC is cytoplasmically localized and has a small serine-rich domain in its COOH terminus that is homologous to the beta-catenin binding site of classical cadherins. Variants of prostate cancer cells that express PCDH-PC have high levels of nuclear beta-catenin protein and increased wnt-signaling. In this study, we show that transfection of human prostate cancer cells (LNCaP) with PCDH-PC or culture of these cells in androgen-free medium (a condition that up-regulates PCDH-PC expression) activates wnt signaling as assessed by nuclear accumulation of beta-catenin, increased expression of luciferase from a reporter vector promoted by Tcf binding elements and increased expression of wnt target genes. Moreover, LNCaP cells transfected with PCDH-PC or grown in androgen-free medium transdifferentiate to neuroendocrine-like cells marked by elevated expression of neuron-specific enolase and chromogranin-A. Neuroendocrine transdifferentiation was also observed when LNCaP cells were transfected by stabilized beta-catenin. Increased wnt signaling and neuroendocrine transdifferentiation of LNCaP cells induced by culture in androgen-free medium was suppressed by short interfering RNAs that target PCDH-PC as well as by dominant-negative Tcf or short interfering RNA against beta-catenin, supporting the hypothesis that increased expression of PCDH-PC is driving neuroendocrine transdifferentiation by activating wnt signaling. These findings have significant implications for the process through which prostate cancers progress to hormone resistance in humans.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-0162DOI Listing
June 2005

A concentrated aglycone isoflavone preparation (GCP) that demonstrates potent anti-prostate cancer activity in vitro and in vivo.

Clin Cancer Res 2004 Aug;10(15):5282-92

Department of Urology, College of Physicians and Surgeons, School of Public Health, Columbia University Medical Center, New York, New York 10032, USA.

Purpose: Isoflavones have anticancer activities, but naturally occurring isoflavones are predominantly glycosylated and poorly absorbed. Genistein combined polysaccharide (GCP; Amino Up Chemical Co., Sapporo, Japan), is a fermentation product of soy extract and basidiomycetes mycillae that is enriched in biologically active aglycone isoflavones. This study analyzes GCP in vitro and in vivo for potential utility as a prostate cancer chemopreventative agent.

Experimental Design: Androgen-sensitive LNCaP and androgen-independent PC-3 cells were grown with various concentrations of GCP. In vitro cell growth was analyzed by the WST-1 assay, and apoptosis was assessed by fluorescence-activated cell sorting and detection of poly(ADP-ribose) polymerase cleavage using Western blot techniques. Effects of GCP on expression of cell cycle-regulatory proteins p53 (LNCaP only), p21, and p27 and the protein kinase Akt were considered using Western blot techniques. An in vivo LNCaP xenograft model was used to study the effects of a 2% GCP-supplemented diet on tumor growth in comparison with a control diet.

Results: GCP significantly suppressed LNCaP and PC-3 cell growth over 72 h (89% and 78% in LNCaP and PC-3, respectively, at 10 microg/ml; P < 0.0001). This reduction was associated with apoptosis in LNCaP cells, but not in PC-3 cells. GCP induced p27 and p53 (LNCaP only) protein expression within 6 h and suppressed phosphorylated Akt in both cell lines. The 2% GCP-supplemented diet significantly slowed LNCaP tumor growth, increasing apoptosis (P < 0.001), and decreasing proliferation (P < 0.001) over 4 weeks.

Conclusions: GCP has potent growth-inhibitory effects against prostate cancer cell lines in vitro and in vivo. These data suggest GCP has potential as an effective chemopreventive agent against prostate cancer cell growth.
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http://dx.doi.org/10.1158/1078-0432.CCR-03-0828DOI Listing
August 2004

Tumor cell hypoxia and the hypoxia-response signaling system as a target for prostate cancer therapy.

Curr Drug Targets 2003 Apr;4(3):191-6

Department of Urology, Columbia University, The College of Physicians and Surgeons, New York, NY 10032, USA.

The accumulation of cancerous cells within a growing prostate tumor can deprive them of adequate vascular support. Without this support, the affected tumor cells become hypoxic, a condition that is usually unfavorable for the further growth and survival of eukaryotic cells. Mammalian cells, however, have the ability of responding to a hypoxic environment by activating a "hypoxia-response" signaling system. Ultimately, this signaling system upregulates the expression of a network of gene products that increase the propensity of the cell to survive even in this adverse environment. With increasing evidence that hypoxia and an activated hypoxia-response signaling system can influence progression (via increased angiogenic propensity and apoptotic resistance) and the therapeutic responsiveness of prostate cancer cells, this review will examine the concept of targeting hypoxia or the hypoxia-response system of prostate tumor cells as a means to suppress prostate tumor progression and metastasis or perhaps even as a means for eliminating prostate tumors in advanced prostate cancer patients.
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http://dx.doi.org/10.2174/1389450033491136DOI Listing
April 2003