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PubMed2001

Efficacy of a single whole-body spray treatment of spinosad, against Boophilus microplus (Acari: Ixodidae) on cattle.

The efficacy of a single whole-body spray of spinosad, a naturally derived control agent, applied at three concentrations was evaluated against cattle infested three separate times prior to treatment and at four weekly intervals following treatment with Boophilus microplus (Canestrini). At 0.0167% active ingredient (AI) both tick numbers (1894 ticks per calf) and index of fecundity (IF) of females (258.3) were no different than that of the control group. However, spinosad treatment at both 0.05 and 0.15% AI resulted in fewer ticks per calf (600 and 935, respectively) with lower IF values for females (43.4 and 38.4, respectively). The percent control of ticks on the animals at the time of treatment (acute efficacy) was dramatically lower at 0.0167% AI (21.4%) than at 0.05 (86.3%) and 0.15% AI (87.9%). Spinosad treatments appeared to be more effective against immature stages (nymphs and larvae) than against adult ticks that were on the animals at the time of treatment. The mean weight of females that survived to repletion was similar (322-348 mg) in all groups. By contrast, the mean weight of egg masses produced by females was highest in the control group (155 mg), whereas each increase in spinosad concentration resulted in a substantial decrease in egg mass weight, with the 0.15% AI group averaging only 73 mg. The hatch rate of eggs derived from females ranged from 93.4% in control females down to 53.9% hatch for females treated at 0.15% AI spinosad. The residual efficacy of spinosad at 0.0167% AI was poor even at 1 week following treatment, resulting in 101 ticks per calf and a level of control of only 66.4%. At 0.05% AI, protection against successful reinfestation was high at 1-week post-treatment where only five ticks per calf reached repletion, and control of the IF of these females was 99.3%. The 0.15% AI treatment provided almost complete protection against reinfestation for 2 weeks following treatment (< or =5 ticks per calf), and control of the IF of these ticks was >99.9%. Thus, the use of spinosad at US ports-of-entry would be unacceptable because of the critical necessity of achieving 100% control with a single treatment to prevent the reintroduction of ticks. However, it is likely ticks could be eradicated using spinosad in tick infested areas of the US if repeated (systematic) treatments were applied to cattle maintained on the premises.

Administration, Topical↗

PubMed1989

Review of the effects of doxazosin, a new selective alpha 1-adrenergic inhibitor, on lipoproteins in patients with essential hypertension.

Control of high blood pressure has failed to reduce the risk of atherosclerotic coronary heart disease (CHD). Hypercholesterolemia, which is common among hypertensive patients, cigarette smoking, and hypertension are the major risk factors for CHD. To minimize CHD risk, elevated blood pressure and atherogenic lipid levels should be lowered, but various antihypertensive agents appear to adversely affect lipid levels, actually precluding the CHD risk reduction expected from blood pressure control. Doxazosin, a once-daily, long-acting, alpha 1-adrenergic inhibitor, not only is effective therapy for essential hypertension but also has a favorable impact on lipids. During controlled studies of doxazosin's antihypertensive efficacy, the following blood lipid levels were measured: total cholesterol, total triglycerides, high-density lipoprotein (HDL) cholesterol (including HDL2 and HDL3), low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein cholesterol, and apoproteins (apos) AI and B. Results showed total cholesterol (-0.8 to -8.9 percent), total triglycerides (-5.0 to -17.4 percent), and LDL (-9.0 to -16.9 percent) were reduced. The positive prognostic indicators, HDL (+0.7 to +13.0 percent) and HDL:total cholesterol ratio (+3.1 to +26.3 percent), were increased. Apo B decreased, but apo AI remained unchanged. In these hypertension studies, doxazosin has favorably reduced two major CHD risk factors. As part of a new, long-term, controlled, multicenter trial, the prospective benefits of these risk factor reductions on CHD morbidity and mortality will be quantified for doxazosin and other antihypertensive agents.

Adrenergic alpha-Antagonists↗

PubMed2005

Adjuvant therapy for breast cancer.

Significant progress has been made in the last 30 years in the adjuvant hormonal and chemo-therapeutic treatments of breast cancer. Currently, several cytotoxic agents are available for use including anthracyclines, taxanes, and cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and a new class of hormonal agents, aromatase inhibitors were introduced. A greater than 50% improvement in risk of relapse and 25% absolute overall survival advantage is presently realistic for many women with lymph node-positive breast cancer who receive adjuvant therapy. Aromatase inhibitors (AI) now constitute a superior alternative to tamoxifen as adjuvant hormonal therapy in postmenopausal women with hormone receptor-positive breast cancer. Extended hormonal therapy with letrozole after completion of five-years of tamoxifen has been shown to improve survival and reduce late relapses. It has also been established that anthracycline containing combination chemotherapy is superior to CMF if the number of cycles is kept the same. Inclusion of a taxane in an anthracycline-based regimen has further improved efficacy. The schedule of administration of drugs, particularly of paclitaxel, also appears to have an impact on efficacy. On the other hand, increasing the dose of cyclophosphamide or anthracyclines above the standard dose do not appear to improve the efficacy of these regimens, whereas substandard dose are clearly inferior. Currently there are several highly effective adjuvant chemotherapy regimens, however there is no single best treatment, let alone a universally effective one. Tamoxifen was the first truly molecularly targeted agent to be used in the treatment of cancer though it took some time to understand that its benefits are restricted to hormone receptor-positive cancers only. Clinical experience shows that similar principals apply to adjuvant chemotherapy as well. Only a subset of patients with micro-metastatic disease benefit from cytotoxic therapy. A major current research effort is focused on the discovery of molecular markers that could predict who will benefit from what particular type of chemotherapy. In the near future, important clinical advances will come from the incorporation of trastuzumab into adjuvant chemotherapy regimens for patients with HER-2 amplified tumors. Results from several large randomized studies are expected shortly and will define the use of trastuzumab in this clinical setting.

Adult↗

PubMed2005

Dalteparin thromboprophylaxis for critically ill medical-surgical patients with renal insufficiency.

PURPOSE: Thromboprophylaxis with low-molecular-weight heparin (LMWH) may be more effective than unfractionated heparin but also more likely to bioaccumulate and potentially cause bleeding in patients with renal insufficiency. The objectives of this study were to assess, among medical-surgical patients in the intensive care unit receiving dalteparin 5,000 IU daily for thromboprophylaxis, (1) the relationship between renal dysfunction and LMWH bioaccumulation as measured by trough anti-Xa levels, (2) the relationship between renal dysfunction and risk of bleeding as measured by a surrogate marker (peak anti-Xa levels), and (3) the relationship between anti-Xa levels, bleeding events, and thrombotic events. MATERIALS AND METHODS: In this prospective single-center cohort study, we enrolled patients 18 years or older, expected to stay 72 hours or longer, and with a creatinine clearance 30 mL/min or higher at intensive care unit admission. We administered 5,000 IU dalteparin subcutaneously each day. The main phase 1 objective was to detect bioaccumulation of dalteparin by measuring trough anti-Xa levels (22-23 hours post dalteparin). The main phase 2 objective was to examine the relationship between renal dysfunction and peak anti-Xa levels (4 hours post dalteparin). We recorded creatinine clearance daily and bleeding and thrombotic events, blinded to anti-Xa levels. RESULTS: We enrolled 19 patients aged 62.7 (13.2) years with an APACHE II score of 23.5 (9.4). We measured trough anti-Xa levels on 185 occasions in 19 patients; we measured peak anti-Xa levels on 113 occasions in 11 patients. We identified no bioaccumulation of LMWH in this study, as detected by trough anti-Xa levels. Most peak anti-Xa levels were in the conventional prophylactic range. CONCLUSIONS: When administered in prophylactic doses to critically ill patients with a wide range of calculated creatinine clearances, we found no evidence of bioaccumulation of dalteparin. If dalteparin does not bioaccumulate, it may be an attractive alternative agent for thromboprophylaxis.

Anticoagulants↗

PubMed2003

Transformation-selective apoptotic program triggered by farnesyltransferase inhibitors requires Bin1.

Neoplastic transformation sensitizes many cells to apoptosis. This phenomenon may underlie the therapeutic benefit of many anticancer drugs, but its molecular basis is poorly understood. We have used a selective and potent farnesyltransferase inhibitor (FTI) to probe a mechanism of apoptosis that is peculiarly linked to neoplastic transformation. While nontoxic to untransformed mouse cells, FTI triggers a massive RhoB-dependent, p53-independent apoptosis in mouse cells that are neoplastically transformed. Here we offer evidence that the BAR adapter-encoding tumor suppressor gene Bin1 is required for this transformation-selective death program. Targeted deletion of Bin1 in primary mouse embyro fibroblasts (MEFs) transformed by E1A+Ras did not affect FTI-induced reversion, actin fiber formation, or growth inhibition, but it abolished FTI-induced apoptosis. The previously defined requirement for RhoB in these effects suggests that Bin1 adapter proteins act downstream or in parallel to RhoB in cell death signaling. The death defect in Bin1 null cells was significant insofar as it abolished FTI efficacy in tumor xenograft assays. p53 deletion did not phenocopy the effects of Bin1 deletion. However, MEFs transformed by SV40 large T antigen+Ras were also resistant to apoptosis by FTI, consistent with other evidence that large T inhibits Bin1-dependent cell death by a p53-independent mechanism. Taken together, the results define a function for Bin1 in apoptosis that is conditional on transformation stress. This study advances understanding of the functions of BAR adapter proteins, which are poorly understood, by revealing genetic interactions with an Rho small GTPase that functions in stress signaling. The frequent losses of Bin1 expression that occur in human breast and prostate cancers may promote tumor progression and limit susceptibility to FTI or other therapeutic agents that exploit the heightened sensitivity of neoplastic cells to apoptosis.

Actins↗

PubMed1996

Proper sequence of endocrine therapies in advanced breast cancer.

Tamoxifen (TAM) is widely used as therapy in early breast cancer and first-line endocrine therapy in metastatic disease. Despite this therapy, many patients relapse and an important question is: What is the preferred sequence of endocrine therapies in metastatic breast cancer (MBC). While treatment with oophorectomy, aminoglutethimide or progestins have been a logical choice after failure to Tamoxifen recent research has extended the options for endocrine therapy of MBC. New selective aromatase inhibitors (AI) are now in clinical use. The first commercially available of these inhibitors is LENTARON. The active ingredient of LENTARON is a steroidal compound 4-OH-androstenedione: Formestane. It is presented as a depot formulation and applied as an i.m. injection of 250 mg every second week. Previous findings from phase II trials have indicated similar activity as other endocrine treatment modalities. Clinical investigations in properly conducted phase III trials have revealed that the efficacy of LENTARON matches the results which can be obtained with TAM and Megace in trials of first and second-line endocrine therapy. Fifty-four and 51% of MBC patients, respectively, did benefit from therapy with LENTARON in these phase III trials by achieving objective responses or stable disease. Moreover, similar overall survival was seen. The systemic tolerability of LENTARON is comparable to that of TAM, and LENTARON seems less systemically toxic than Megace. Local side effects occured in approximately 7% of the patients giving rise mainly to pain or inflammation at the injection site. In elderly patients, LENTARON therapy assures compliance and no interference with other oral medications has been observed. In conclusion, since the endocrine treatment modalities are comparable in terms of efficacy the optimal sequence of these treatments is based upon differences in tolerability. Patients previously treated with Tamoxifen and with a high probability of a further endocrine response could preferably be treated with a selective AI like LENTARON as second-line endocrine therapy followed by a progestin upon progression in responders.

Androstenedione↗

PubMed2004

Adjuvant aromatase inhibitors following tamoxifen for early-stage breast cancer in postmenopausal women: what do we really know?

Adjuvant hormonal therapy in the treatment of women with early-stage, hormone receptor (HR)-positive breast cancer is now considered the standard of care. Adjuvant tamoxifen decreases the risk of breast cancer recurrence and death in women with early-stage breast cancer when taken for 5 years. The benefits of tamoxifen are counterbalanced by toxicities including an increased risk of endometrial cancer and thromboembolic events. The selective aromatase inhibitors (AIs)--including anastrozole, letrozole, and exemestane--are challenging the role of tamoxifen as the adjuvant hormonal therapy of choice in postmenopausal women. Results of the Arimidex and Tamoxifen Alone or in Combination trial favor the use of anastrozole over tamoxifen as initial adjuvant hormonal therapy, with improvement in disease-free survival (DFS) and a favorable toxicity profile. The results of 2 large adjuvant trials using AIs sequentially with tamoxifen in postmenopausal women with early-stage, HR-positive breast cancer have been reported. The MA-17 study randomized women to placebo or letrozole for 5 years after completion of 4.5-6 years of initial tamoxifen. The Intergroup Exemestane Study (IES) randomized women following 2-3 years of adjuvant tamoxifen to continue to receive tamoxifen or switch to exemestane for a total of 5 years of adjuvant hormonal therapy. The MA-17 and IES trials demonstrated superior DFS with the AI and corroborated the smaller GROCTA-4B and Italian Tamoxifen Arimidex trials, which studied sequential therapy with aminoglutethamide or anastrozole. There is now substantial medical evidence supporting the use of AIs in postmenopausal women with early-stage, HR-positive breast cancer.

Aged↗

PubMed2004

Implications of first-line adjuvant treatment with aromatase inhibitors in recurrent metastatic breast cancer.

The role of adjuvant tamoxifen therapy has gone unchallenged until recently. With the introduction of the selective aromatase inhibitors (AIs), the paradigm for treatment of hormone receptor-positive breast cancer in postmenopausal women is changing. New data from randomized clinical trials have shown the impact of the use of an AI compared with tamoxifen or in sequence with tamoxifen. This review will emphasize some of the highlights from these data sets and the limitations of our current knowledge. Finally, we will discuss the implications of the use of nonselective AIs in the adjuvant setting for the patient who develops recurrent metastatic disease.

Aged↗

PubMed2005

Aromatase inhibitors in postmenopausal breast cancer patients.

Aromatase inhibitors (AIs) have greatly enriched the treatment of hormone receptor-positive breast cancer in postmenopausal patients. Before the introduction of the well-tolerated third-generation AIs, tamoxifen was the mainstay of endocrine therapy for hormone receptor-positive breast cancer. Many clinical trials have shown the superiority of AIs compared with tamoxifen in adjuvant breast cancer treatment, as well as their benefit in metastatic breast cancer. NCCN guidelines recommendations for their use are based on the evidence provided by these clinical trials. This discussion reviews the evidence supporting the current guidelines for use of AI therapy in the treatment of hormone receptor-positive postmenopausal breast cancer patients.

Antineoplastic Agents↗

PubMed1998

Inhibition of angiogenesis on glycated collagen lattices.

Advanced glycation endproduct (AGE) accumulation in extracellular matrix proteins has been demonstrated in diabetic patients with a significant correlation with the severity of diabetic complications. AGE accumulation induces matrix protein cross-link formation, resulting in an increased stiffness of matrix fibres and the reduction of the susceptibility of matrix proteins to proteolytic degradation. We examined whether glycation-induced collagen cross-linking may affect vascular endothelial cell behaviours such as invasion, proliferation and differentiation, using the in vitro angiogenesis model of capillary-like structure formation in three-dimensional matrices of collagen type I. Endothelial cells cultured on collagen gel with angiogenic factors (the combination of fibroblast growth factor-2 and vascular endothelial growth factor) invaded the underlying collagen matrix, and organized capillary-like cord structures in the gel. We found that endothelial cell invasion into glycated collagen gel was significantly attenuated without any effect on proteinase activity including cell-associated plasminogen activator and matrix metalloproteinase in the conditioned medium. In addition, subsequent capillary-like cord formation was also inhibited in glycated collagen gel. In contrast, endothelial cell proliferation was enhanced on glycated collagen gel with or without angiogenic factors compared with control collagen gel. These results suggest that the structural alterations of extracellular matrix proteins through the glycation-induced cross-link formation affect the interaction between endothelial cell and extracellular matrix, resulting in the impairment of an adequate neovascularization in diabetic patients.

Angiogenesis Inducing Agents↗

PubMed2006

Antipsychotics improve Delta9-tetrahydrocannabinol-induced impairment of the prepulse inhibition of the startle reflex in mice.

Recently, cannabinoid receptor agonists have been reported to impair prepulse inhibition (PPI) of the startle reflex. In the current study, we examined the effect of Delta9-tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, on the PPI, and found that THC (10 mg/kg, i.p.) impaired the PPI concomitant with a decrease in the startle response. Antipsychotics such as haloperidol (0.3 mg/kg, i.p.) and risperidone (0.1 mg/kg, i.p.), which are potent dopamine D2 receptor antagonists, and SR141716 (10 mg/kg, i.p.), a CB1 cannabinoid receptor antagonist, reversed these THC-induced PPI deficits. Moreover, THC (10 mg/kg) increased dopamine (DA) release in the nucleus accumbens but not medial prefrontal cortex over a 50-100-min period (time of PPI test) after treatment, and SR141716 (10 mg/kg) reversed this increase in DA release induced by THC. These results suggest that dopaminergic hyperfunction in the nucleus accumbens may be involved in THC-induced PPI deficits.

Acoustic Stimulation↗

PubMed2005

ent-Kaurane Diterpenoids from Isodon albopilosus.

Nine new diterpenoids, albopilosins B-J (1-9), together with six known analogues, albopilosin A (10), macrocalyxin C (11), rabdokunmin C (12), excisanin (13), amethystonoic acid (14), and coetsanoic acid (15), were isolated from the aerial parts of Isodon albopilosus. The structures of 1-9 were established using spectroscopic methods including extensive 1D and 2D NMR analysis. The diterpenoids isolated were evaluated for their inhibitory activities against HepG2 (hepatoma) cells. Compounds 7 and 13 were the most active, with both having IC(50) values of <15 microM.

Antineoplastic Agents, Phytogenic↗

PubMed2005

Cytotoxic and antifungal isoprenylated xanthones and flavonoids from Cudrania fruticosa.

A new isoprenylated xanthone, cudrafrutixanthone A, was isolated from the roots of Cudrania fruticosa, together with 18 known compounds. Their structures were elucidated by spectroscopic methods. Most isoprenylated xanthones exhibited cytotoxicity against HCT-116, SMMC-7721, SGC-7901, and BGC-823 cell lines with IC (50) values of 1 - 5 microg/mL. Toxyloxanthone C and wighteone showed antifungal activity against Candida albicans with MICs of 25 and 12.5 microg/mL, respectively.

Antifungal Agents↗

PubMed2005

Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors.

BACKGROUND: Whether bone markers have prognostic value in patients with bone metastases is unknown. We investigated this question in patients with bone metastases secondary to prostate cancer and to non-small-cell lung cancer (NSCLC) and other solid tumors assigned to the placebo arms of two phase III trials of zoledronic acid. METHODS: Levels of the urinary bone resorption marker N-telopeptide and the serum bone formation marker bone-specific alkaline phosphatase were assessed every 3 months for patients with prostate cancer (n = 203) or NSCLC or other solid tumors (n = 238) and were categorized as low or high. Patients were monitored for skeletal-related events, bone disease progression, and death. The relative risks (RRs) and 95% confidence intervals (CIs) for these outcomes were estimated for patients with high versus low levels of each marker using intensity-based multiple event and Cox regression models. All statistical tests were two-sided. RESULTS: In each disease group and overall, high levels of each marker at the beginning of the study were statistically significantly associated with an increased risk of negative outcomes. Use of recent marker assessments as time-dependent covariates gave even greater prognostic significance. High N-telopeptide levels were a stronger prognostic indicator of negative outcomes than bone-specific alkaline phosphatase levels. In recent assessments, patients with high N-telopeptide levels had an increased relative risk of skeletal-related events (prostate cancer, RR = 3.25, 95% CI = 2.26 to 4.68, P<.001; NSCLC and other solid tumors, RR = 1.79, 95% CI = 1.15 to 2.79, P = .010), disease progression (prostate cancer, RR = 2.02, 95% CI = 1.48 to 2.74, P<.001; NSCLC and other solid tumors, RR = 1.91, 95% CI = 1.16 to 3.15, P = .011), and death (prostate cancer, RR = 4.59, 95% CI = 2.82 to 7.46, P<.001; NSCLC and other solid tumors, RR = 2.67, 95% CI = 1.85 to 3.85, P<.001) compared with patients with low N-telopeptide levels. CONCLUSIONS: Baseline and recent bone marker levels were predictive of negative clinical outcomes in patients with bone metastases secondary to prostate cancer and to NSCLC and other solid tumors. N-telopeptide levels were more consistent prognostic indicators than bone-specific alkaline phosphatase for all tumor types, reflecting the key role of osteolysis in the development of skeletal complications.

Adult↗

PubMed2003

[A successful treatment of progressive necrotizing myositis caused by Aeromonas veronii biotype sobria].

We report a 52 year-old patient with malignant lymphoma who developed necrotizing soft tissue infection in the left lower extremity by Aeromonas veronii biotype sobria during a neutropenic period after intensive chemotherapy. We decided to amputate the involved leg when signs and symptoms of necrotizing myositis were progressing despite administration of sensitive antibiotics. He survived with subsequent intensive supportive care. It is to note that even though the patient's neutrophil count is zero, he or she should be treated aggressively by drainaging the lesion or even amputation of the involved extremities in combination with proper antibiotics.

Aeromonas↗

PubMed2003

Tanshinone (Salviae miltiorrhizae extract) preparations attenuate aminoglycoside-induced free radical formation in vitro and ototoxicity in vivo.

Antioxidant therapy protects against aminoglycoside-induced ototoxicity in animal models. A clinically suitable antioxidant must not affect the therapeutic efficacy of aminoglycosides or exhibit any side effects of its own. In addition, the treatment should be inexpensive and convenient in order to be implemented in developing countries where the use of aminoglycosides is most common. Standardized Salviae miltiorrhizae extracts (Danshen) are used clinically in China and contain diterpene quinones and phenolic acids with antioxidant properties. We combined in vitro and in vivo approaches to investigate the effect of a clinically approved injectable Danshen solution on aminoglycoside-induced free radical generation and ototoxicity. In vitro, Danshen inhibited gentamicin-dependent lipid peroxidation (formation of conjugated dienes from arachidonic acid), as well as the gentamicin-catalyzed formation of superoxide (in a lucigenin-based chemiluminescence assay) and hydroxyl radicals (oxidation of N,N-dimethyl-p-nitrosoaniline). Danshen extracts were then administered to adult CBA mice receiving concurrent treatment with kanamycin (700 mg/kg of body weight twice daily for 15 days). Auditory threshold shifts induced by kanamycin (approximately 50 dB) were significantly attenuated. Danshen did not reduce the levels in serum or antibacterial efficacy of kanamycin. These results suggest that herbal medications may be a significantly underexplored source of antidotes for aminoglycoside ototoxicity. Such traditional medicines are widely used in many developing countries and could become an easily accepted and inexpensive protective therapy.

Abietanes↗

PubMed2002

Simultaneous in situ monitoring of intracellular Ca2+ and NO in endothelium of coronary arteries.

We developed an in situ assay system to simultaneously monitor intracellular Ca(2+) concentration ([Ca(2+)](i), fura 2 as indicator) and nitric oxide (NO) levels [4,5-diaminofluorescein as probe] in the intact endothelium of small bovine coronary arteries by using a fluorescent microscopic imaging technique with high-speed wavelength switching. Bradykinin (BK; 1 microM) stimulated a rapid increase in [Ca(2+)](i) followed by an increase in NO production in the endothelial cells. The protein tyrosine phosphatase inhibitor phenylarsine oxide (PAO; 10 microM) induced a gradual, small increase in [Ca(2+)](i) and a slow increase in intracellular NO levels. Removal of extracellular Ca(2+) and depletion of Ca(2+) stores completely blocked BK-induced increase in NO production but had no effect on PAO-induced NO production. However, a further reduction of [Ca(2+)](i) by application of BAPTA-AM or EGTA with ionomycin abolished the PAO-induced NO increase. These results indicate that a simultaneous monitoring of [Ca(2+)](i) and intracellular NO production in the intact endothelium is a powerful tool to study Ca(2+)-dependent regulation of endothelial nitric oxide synthase, which provides the first direct evidence for a permissive role of Ca(2+) in tyrosine phosphorylation-induced NO production.

Animals↗

PubMed2006

Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells.

Cyclooxygenase-2 (COX-2) is antiapoptotic and is implicated in tumorigenesis. Recent reports, however, have also ascribed a proapoptotic action to inducible COX-2. We show here for the first time that a stilbene, resveratrol, induces nuclear accumulation of COX-2 protein in human breast cancer MCF-7 and MDA-MB-231 cell cultures. The induction of COX-2 accumulation by resveratrol is mitogen-activated protein kinase (MAPK; extracellular signal-regulated kinase 1/2)- and activator protein 1- dependent. Nuclear COX-2 in resveratrol-treated cells colocalizes with Ser(15)-phosphorylated p53 and with p300, a coactivator for p53-dependent gene expression. The interaction of COX-2, p53, and p300, as well as resveratrol-induced apoptosis, was inhibited by a MAPK activation inhibitor, PD98059. A specific inhibitor of COX-2, NS398, and small interfering RNA knockdown of COX-2 were associated with reduced p53 phosphorylation and consequent decrease in p53-dependent apoptosis in resveratrol-treated cells. We conclude that nuclear accumulation of COX-2 can be induced by resveratrol and that the COX has a novel intranuclear colocalization with Ser(15)-phosphorylated p53 and p300, which facilitates apoptosis in resveratrol-treated breast cancer cells.

Antineoplastic Agents, Phytogenic↗