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Effective Cancer Therapies (effective + cancer_therapy)
Selected AbstractsRNAi-mediated MEK1 knock-down prevents ERK1/2 activation and abolishes human hepatocarcinoma growth in vitro and in vivoINTERNATIONAL JOURNAL OF CANCER, Issue 6 2010Luc Gailhouste Abstract The mitogen-activated protein kinases MEK/ERK pathway regulates fundamental processes in malignant cells and represents an attractive target in the development of new cancer treatments especially for human hepatocarcinoma highly resistant to chemotherapy. Although gene extinction experiments have suggested distinct roles for these proteins, the MEK/ERK cascade remains widely considered as exhibiting an overlap of functions. To investigate the functionality of each kinase in tumorigenesis, we have generated stably knock-down clones for MEK1/2 and ERK1/2 isoforms in the human hepatocellular carcinoma line HuH7. Our results have shown that RNAi strategy allows a specific disruption of the targeted kinases and argued for the critical function of MEK1 in liver tumor growth. Transient and stable extinction experiments demonstrated that MEK1 isoform acts as a major element in the signal transduction by phosphorylating ERK1 and ERK2 after growth factors stimulation, whereas oncogenic level of ERK1/2 phosphorylation appears to be MEK1 and MEK2 dependent in basal condition. In addition, silencing of MEK1 or ERK2 abolished cell proliferation and DNA replication in vitro as well as tumor growth in vivo after injection in rodent. In contrast, targeting MEK2 or ERK1 had no effect on hepatocarcinoma progression. These results strongly corroborate the relevance of targeting the MEK cascade as attested by pharmacologic drugs and support the potential application of RNAi in future development of more effective cancer therapies. Our study emphasizes the importance of the MEK/ERK pathway in human hepatocarcinoma cell growth and argues for a crucial role of MEK1 and ERK2 in this regulation. [source] Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes,CANCER, Issue 4 2008Results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB) Abstract BACKGROUND. Epidermal growth factor receptor (EGFR) inhibitors are effective cancer therapies, but they are reported to cause a rash in >50% of patients. In the current study, the authors examined the use of tetracycline for rash prevention. METHODS. This placebo-controlled, double-blinded trial enrolled patients who were starting cancer treatment with an EGFR inhibitor. Patients could not have had a rash at the time of enrollment. All patients were randomly assigned to receive either tetracycline at a dose of 500 mg orally twice a day for 28 days versus a placebo. Patients were monitored for rash (through monthly physician assessment and weekly patient-reported questionnaires), quality of life (using the SKINDEX-16, a skin-specific quality of life index), and adverse events. Monitoring occurred during the 4-week intervention and then for an additional 4 weeks. The primary objective of the current study was to compare the incidence of rash between the study arms, and the enrollment of 30 patients per arm provided a 90% probability of detecting a 40% difference in incidence with a P value of .05 (2-sided). RESULTS. A total of 61 evaluable patients were enrolled. The 2 treatment arms were well balanced with regard to baseline characteristics, dropout rates, and rates of discontinuation of the EGFR inhibitor. The incidence of rash was found to be comparable across treatment arms. Physicians reported that 16 patients treated with tetracycline (70%) and 22 patients treated with placebo (76%) developed a rash (P = .61). Tetracycline appears to have lessened the rash severity, although the high dropout rates invite caution when interpreting these findings. By Week 4, physician-reported grade 2 rash (using the National Cancer Institute's Common Terminology Criteria for Adverse Events [version 3.0]) occurred in 17% of tetracycline-treated patients (n = 4 patients) and in 55% of placebo-exposed patients (n = 16 patients) (P = .04). Patients treated with tetracycline reported better scores, as per the SKINDEX-16, on certain quality-of-life parameters such as skin burning or stinging, skin irritation, and being bothered by the persistence/recurrence of a skin condition. Adverse events were found to be comparable across treatment arms. CONCLUSIONS. In the current study, tetracycline was not found to prevent EGFR inhibitor-induced rashes and therefore cannot be clinically recommended for this purpose. However, preliminary observations of diminished rash severity and improved quality of life suggest this antibiotic merits further study. Cancer 2008. © 2008 American Cancer Society. [source] Trafficking and localization of platinum complexes in cisplatin-resistant cell lines monitored by fluorescence-labeled platinum,JOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2005Xing-Jie Liang Cisplatin is a chemotherapeutic agent commonly used in the treatment of a wide variety of malignant tumors. Resistance to cisplatin represents a major obstacle to effective cancer therapy because clinically significant levels of resistance quickly emerge after treatment. Based on previous studies indicating abnormal plasma membrane protein trafficking in cisplatin-resistant (CP-r) cells, Fluorescence (Alexa Fluor)-labeled cisplatin was used to determine whether this defect altered the trafficking and localization of cisplatin by comparing drug sensitive KB-3-1 and KB-CP-r cells. Alexa Fluor,cisplatin was readily internalized and localized throughout the KB-3-1 cells, but overall fluorescence decreased in KB-CP-r cells, as detected by flow cytometry (FACS) and confocal microscopy. Only punctate cytoplasmic staining was observed in KB-CP-r cells with less fluorescence observed in the nucleus. Colocalization experiments with a Golgi-selective stain indicate the involvement of Golgi-like vesicles in initial intracellular processing of Alexa Fluor conjugated cisplatin complexes. As detected using an antibody to Alexa Fluor,cisplatin, cisplatin complex-binding proteins (CCBPs) were reduced in membrane fractions of single-step cisplatin-resistant KB-CP.5 cells, and increased in the cytoplasm of KB-CP.5 cells compared to KB-3-1 cells. CCBPs localized to lower density fractions in KB-CP.5 cells than in KB-3-1 cells as determined by iodixanol gradient centrifugation. In summary, inappropriate trafficking of CCBPs might explain resistance to cisplatin in cultured cancer cells, presumably because membrane binding proteins for cisplatin are not properly located on the cell surface in these cells, but are instead trapped in low density vesicles within the cytoplasm. © 2004 Wiley-Liss, Inc. [source] Hypoxia-inducible factor-1, contributes to hypoxia-induced chemoresistance in gastric cancerCANCER SCIENCE, Issue 1 2008Lili Liu Hypoxia induced drug resistance is a major obstacle in the development of effective cancer therapy. Our previous study revealed that hypoxia-inducible factor-1 (HIF-1), the major transcriptional factor significantly activated by hypoxia, was overexpressed in gastric vincristine-resistant cells SGC7901/vincristine (VCR) under normoxic conditions, which suggested that it was associated with drug resistance in gastric cancer cells. In the present study, a colony-forming assay revealed that hypoxia and forced HIF-1, expression increased maximal ,8.9-fold or ,14.8-fold of IC50 toward vincristine in gastric cancer cell lines SGC7901 and SGC7901/VCR, respectively (P < 0.01). Annexin-V/propidium iodide staining analysis revealed hypoxia or forced HIF-1, expression reduced apoptosis by 24% or 18% in SGC7901 cells (P < 0.05). Flow cytometry analysis of intracellular adriamycin revealed that hypoxia and forced expression of HIF-1, increased ,1.79-fold or ,2.36-fold of the adriamycin releasing index, respectively (P < 0.05). However, resistance acquisition subject to hypoxia in vitro and in vivo was suppressed by blocking HIF-1, expression with siRNA. We further demonstrated that HIF-1 , overexpression showed a 1.85-fold increased expression of Bcl-2 and a 2.16-fold decreased expression of Bax, and also showed significantly induced expression of p-gp and MRP1, which indicated that HIF-1, may confer hypoxia-induced drug resistance via inhibition of drug-induced apoptosis and decreases in intracellular drug accumulation. (Cancer Sci 2008; 99: 121,128) [source] | ||||||||||