Curcumin induces apoptosis and inhibits growth of orthotopic human non-small cell lung cancer xenografts.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality. Curcumin is involved in various biological pathways leading to inhibition of NSCLC growth. The purpose of this study was to evaluate the effect of curcumin on expression of nuclear factor κB-related proteins in vitro and in vivo and on growth and metastasis in an intralung tumor mouse model. H1975 NSCLC cells were treated with curcumin (0-50 µM) alone, or combined with gemcitabine or cisplatin. The effects of curcumin were evaluated in cell cultures and in vivo, using ectopic and orthotopic lung tumor mouse models. Twenty mice were randomly selected into two equal groups, one that received AIN-076 control diet and one that received the same food but with the addition of 0.6% curcumin 14 days prior to cell implantation and until the end of the experiment. To generate orthotopic tumor, lung cancer cells in Matrigel were injected percutaneously into the left lung of CD-1 nude mice. Western blot analysis showed that the expressions of IkB, nuclear p65, cyclooxygenase 2 (COX-2) and p-ERK1/2 were down-regulated by curcumin in vitro. Curcumin potentiated the gemcitabine- or cisplatin-mediated antitumor effects. Curcumin reduced COX-2 expression in subcutaneous tumors in vivo and caused a 36% decrease in weight of intralung tumors (P=.048) accompanied by a significant survival rate increase (hazard ratio=2.728, P=.036). Curcumin inhibition of COX-2, p65 expression and ERK1/2 activity in NSCLC cells was associated with decreased survival and increased induction of apoptosis. Curcumin significantly reduced tumor growth of orthotopic human NSCLC xenografts and increased survival of treated athymic mice. To evaluate the role of curcumin in chemoprevention and treatment of NSCLC, further clinical trials are required.

Targeting ErbB-1 and ErbB-4 in irradiated head and neck cancer: results of in vitro and in vivo studies.

BACKGROUND: ErbB oncogenes have a major role in cancer. The role of ErbB-4 in cancer cell biology and the effect of anti-ErbB-1 and anti-ErbB-4 monoclonal antibodies were evaluated in this study. METHODS: ErbB-4 expression and binding was evaluated by Western blot, enzyme-linked immunosorbent assay (ELISA), fluorescent microscopy, and flow cytometry. Cell survival was measured by XTT assay. Tumor progression was followed up in nude mice model. RESULTS: High ErbB-1 levels in head and neck cancer cell lines were determined, whereas ErbB-4 expression varied. Specific antibody binding to the cells was demonstrated. High ErbB-4 expressing squamous cell carcinoma 1 (SCC-1) cells proliferated faster and generated faster growing tumors in mice. Cetuximab and mAb-3 reduced cell survival proportional to ErbB-1 and ErbB-4 expression. Combination of antibodies with irradiation was most effective in reducing cell survival and tumor growth. CONCLUSION: ErbB-4 plays a role in head and neck cancer cell biology. Anti-ErbB-4 targeted therapy can serve as a new strategy against head and neck cancer when combined with established treatments.

Treatment of earlobe keloids by extralesional excision combined with preoperative and postoperative "sandwich" radiotherapy.

BACKGROUND: Earlobe keloids can form after cosmetic ear piercing, trauma, infection, or burns, or spontaneously. These keloids are highly resistant for treatment and are followed by severe cosmetic implications. There are various surgical and nonsurgical treatment modalities for earlobe keloids, with no universally accepted treatment policy and a wide range of reported recurrence rates. The authors present their experience of treating earlobe keloids using the "sandwich" technique protocol; extralesional excision and external-beam radiotherapy are given a day before and a day after the operation. METHODS: The authors retrospectively reviewed all patients with earlobe keloids treated by the "sandwich" technique between the years 1996 and 2005. Patients were categorized into two groups: a high-risk group for previously treated patients and patients with a tendency for hypertrophic scars and keloids, and a low-risk group for the others. All patients underwent extralesional excision of the keloid and local radiotherapy before the excision and following it. Follow-up was a minimum of half a year and included a patient satisfaction questionnaire and documentation of keloid recurrence or cure. RESULTS: A total of 23 patients were treated by this protocol; 57 percent were male. Patients had an average age of 24 years. The most common keloid etiology was earlobe piercing. Recurrence rates for the low-risk and high-risk groups were 25 and 27 percent [percent of the patients], respectively. Overall patient satisfaction was high. CONCLUSION: The combined excision and "sandwich" radiotherapy technique is a simple and effective method for treating earlobe keloids, with high patient satisfaction and low recurrence and complication rates.

Curcumin: a potential radio-enhancer in head and neck cancer.

OBJECTIVES/HYPOTHESIS: To investigate whether curcumin enhances the cytotoxic effect of radiotherapy in head and neck squamous cell carcinoma (HNSCC). METHODS: HNSCC cell lines SCC-1, SCC-9, KB, as well as A431 cell line were treated with curcumin, irradiation, or their combination. Cell viability was evaluated by XTT assay. Cyclooxygenase-2 (COX-2), epithelial growth factor receptor (EGFR), and p-Erk1/2 were measured by Western blot analysis. CD-1 athymic nude mice with orthotopic implanted SCC-1 cells, were treated with control diet, curcumin containing diet, local single-dose radiation, or combination. RESULTS: Curcumin (IC50 range, 15-22 microM) and radiation inhibited cell viability in all cell lines were tested. The combination of curcumin and radiation resulted in additive effect. Curcumin decreased COX-2 expression and inhibited phosphorylation of EGFR in SCC-1 cells. In tumor-bearing mice the combination regimen showed a decrease in both tumor weight (25%, P = .09) and tumor size (15%, P = .23) compared to the nontreated mice. CONCLUSIONS: : Curcumin inhibited HNSCC cell growth and augmented the effect of radiation in vitro and in vivo. A possible mechanism is inhibition of COX-2 expression and EGFR phosphorylation.

Invasive breast cancer treated with taxol and epirubicin neo-adjuvant chemotherapy: the role in the outcome of the "crosstalk" between Erb receptors and p53.

PURPOSE: To correlate p53 and ErbB receptors status with disease-free survival (DFS) and overall survival (OS) in locally advanced breast cancer. PATIENTS AND METHODS: Sixty patients were included in a single-center, open-label, phase II trial (1998-2003). Analysis of Erb receptors and p53 status and estrogen receptor/progesterone receptor data were available for 33 patients. Neoadjuvant epirubicin 75 mg/m2 and paclitaxel 175-200 mg/m2 were administered every 21 days. The patients underwent surgery and radiation therapy and adjuvant chemo/hormonotherapy. RESULTS: Approximately two thirds of the patients demonstrated overexpression of ErbB receptors and had mutant p53 overexpression. The disease recurred in 11/33 patients and 7 died (median follow-up 56 months). Detrimental effects on OS were established in cases of combined defective p53 expression and ErbB1-ErbB3 heterodimeric receptor overexpression. In contrast, normal p53 together with the same overexpressed heterodimeric combination of ErbB receptors showed no statistically significant effect. CONCLUSION: In terms of the clinical impact of combinations of ErbB receptors with or without mutant p53, only the overexpressed various ErbB1-ErbB3 dimeric combinations and the ErbB1/ErbB2/ErbB3 triplet combination with mutated p53 were related to a significantly poorer outcome. This observation may help in the development of new strategies required for blocking these molecular pathways and improving the outcome of patients with locally advanced breast cancer.

Fulvestrant in heavily pretreated metastatic breast cancer: is it still effective as a very advanced line of treatment?

BACKGROUND: Over 75% of postmenopausal patients with metastatic breast cancer have hormone receptor-positive tumors. Endocrine therapy, with its more favorable toxicity profile than chemotherapy, is the preferred treatment modality for these patients. OBJECTIVES: To assess our experience with fulvestrant, an antiestrogen, in an advanced phase of treatment, after progression on the classical anti-estrogen (tamoxifen) and aromatase inhibitors METHODS: The study group comprised 46 patients with metastatic breast cancer treated with fulvestrant during the years 2002-2006. Fulvestrant was given monthly until disease progression or unacceptable toxicity. RESULTS: The median number of fulvestrant cycles was 4.14 (range 1-32). Four patients are still on the treatment. The reasons for treatment discontinuation include disease progression (n=40), refusal (n=1), and allergic reaction (n=1). Ten patients (22%) achieved partial response and 22 (47%) had stable disease. Fourteen (30%) had disease progression with a response rate of 22% and a clinical benefit of 67%, and 14 (30%) had stable disease for > 6 months. Twenty-five patients (54%) are still alive, 4 (9%) without and 21 (45%) with disease progression. With a median follow-up of 15 months (range 1-30.1), the median time to progression was estimated to be 4 months (95% confidence interval 3.1-4.9), and the estimated overall survival 20.1 (95% CI 13.6 to upper limit; not reached yet). The 1 year estimated survival is 67%. CONCLUSIONS: In terms of late-phase administration, fulvestrant still appears to have a good clinical effect, with a time to progression of 4 months and a clinical benefit > 60%, notably accompanied by only very mild toxicity. Irrespective of the line of treatment the patients received, the 4 month time to progression was constant and the medication was still working effectively in a very late line of treatment in metastatic breast cancer. Fulvestrant offers clinical benefit with very mild toxicity in a very heavily pretreated population and the medication is recommended, even in patients who received many lines of chemotherapy.

Anti-ERBb4 targeted therapy combined with radiation therapy in prostate cancer. Results of in vitro and in vivo studies.

PURPOSE: To evaluate the efficiency of anti ErbB4 targeted therapy combined with irradiation (XRT) over each modality alone in prostate cancer. RESULTS: Clones with high ErbB4 expression grew faster than those with low ErbB4 expression. XRT inhibited the growth of both expressive and non-expressive ErbB4 cells, while mAb inhibited only high ErbB4-expressing cells. The combination of XRT and mAb resulted in a 30% reduction of the survival of high ErbB4 expressing cells over XRT alone (p = 0.013). In tumor bearing mice the tumor size in the combined arm was 1 mm at 4 weeks compared to 2-3 mm and 4-5 mm in the radiation and mAb arms (p' value of 0.02 and 0.087 respectively). METHODS: Clones with low and high expression of ErbB4 isolated by a limited dilution technique from an androgen-independent Cl-1 cell line were used. The cells from these clones were exposed to XRT (single dose of 2-6 Gy) and to anti-ErbB4 monoclonal antibody (mAb). The XTT test was used to measure cell survival. In addition, tumor-bearing nude mice were treated either by XRT, mAb or by a combined treatment. Tumor sizes were recorded at given time points. CONCLUSION: Anti ErbB4 combined with XRT is possibly more effective than each modality alone in prostate cancer.

Elective paratracheal neck dissection for lateral metastases from papillary carcinoma of the thyroid: is it indicated?

BACKGROUND: Therapeutic paratracheal neck dissection for patients with papillary carcinoma of the thyroid is standard treatment. Its use as an elective procedure is controversial. METHODS: Thirty-seven patients with papillary carcinoma of the thyroid and evidence of positive adenopathy at levels II-V underwent selective neck dissection and elective/therapeutic paratracheal neck dissection. Results of preoperative ultrasonography of the neck were compared with the dissection specimens. RESULTS: Morbidity of the surgical procedure was minimal (1 permanent hypocalcemia). All specimens showed metastases from papillary thyroid carcinoma: 100% (37/37) in the jugular chain of lymphatics and 83.7% (31/37) in the paratracheal region. The rate of occult (negative physical examination and ultrasonography) metastases in the paratracheal region in the presence of metastases in the ipsilateral jugular chain was 83.3% (20/24). CONCLUSION: The high rate of occult metastases in the paratracheal region and the low rate of surgical morbidity speak in favor of elective paratracheal neck dissection in patients with metastatic papillary carcinoma of the thyroid.

The sensitivity of preoperative scanning in regional recurrence of papillary thyroid cancer.

BACKGROUND: The treatment of patients with regionally recurrent papillary carcinoma of the thyroid is a matter of controversy. Radioactive nodal picking was proposed as an alternative to neck dissection in these patients. METHODS: We analyzed neck dissection specimens in 20 patients with PTC and compared the results to preoperative total-body scan (TBS) following a therapeutic dose of I(131)and ultrasonographic findings. RESULTS: Eighteen patients underwent paratracheal neck dissection and 10 patients had a lateral neck dissection. Preoperative TBS detected the correct number of positive nodes in only 1 patient (5%) and the correct number of patients with positive nodes in 6/20 (30%) of the patients. US detected 32/98 positive nodes (36%) and 20/20 (100%) of the patients. Prediction of the number of positive nodes for both TBS and US was low (5% and 10%, respectively). CONCLUSIONS: Preoperative TBS and/or US cannot satisfactorily predict metastatic lymph node involvement and cannot safely delineate limited surgery to replace formal neck dissection in patients with regionally recurrent PTC.

Curcumin augments gemcitabine cytotoxic effect on pancreatic adenocarcinoma cell lines.

BACKGROUND AND AIM: Gemcitabine, the first-line agent in pancreatic adenocarcinoma, has shown limited clinical benefit. Cyclooxygenase-2 (COX-2) represent one of the most promising targets for cancer prevention and treatment. In this study, we investigated whether the phytochemical curcumin, a natural COX-2 inhibitor, can potentiate gemcitabine effect on survival of human pancreatic cancer cells. METHODS: P34 (high COX-2 expression) and Panc-1 (low COX-2 expression) pancreatic cancer cell lines were exposed to different concentrations of gemcitabine (0.1-10 microM), curcumin (0-50 microM), and their combination. Cell viability was evaluated by XTT assay. Cell cycle and apoptosis were assessed by flow cytometry. COX-2, EGFR, and p-ERK1/2 expression was measured by Western blot analysis. RESULTS: Curcumin increased the inhibitory effect of gemcitabine on cell viability as well as its pro-apoptotic effect in COX-2 positive, p34 cells, but not in COX-2 negative, Panc-1 cells. In p34 cells, combination of curcumin and gemcitabine downregulated both COX-2 and p-ERK1/2 in a dose-dependent manner. CONCLUSION: The increased cytotoxic effect of the combination on cell survival and on the induction of apoptosis in COX-2 expressing pancreatic cancer cells is probably associated with downregulation of COX-2 and p-ERK1/2 levels. This finding may contribute to the development of an effective treatment of pancreatic adenocarcinoma.