Discovery of New Glucose Uptake Inhibitors as Potential Anticancer Agents by Non-Radioactive Cell-Based Assays.

Tumor cells rely on aerobic glycolysis to support growth and survival, thus require more glucose supply. Glucose transporters GLUTs, primarily GLUT1, are overexpressed in various cancers. Targeting GLUTs has been regarded as a promising anticancer strategy. In this study, we first evaluated 75 potential GLUT1 inhibitors obtained from virtual screening of the NCI chemical library by a high-throughput cell-based method using a fluorescent glucose analogue 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy-d-glucose (2-NBDG) in COS-7 and SKOV3 cells that express high levels of GLUT1. Four compounds, #12, #16, #43 and #69, that significantly inhibited glucose uptake were further evaluated using flow cytometry directly measuring 2-NBDG uptake at the single-cell level and a Glucose Uptake-GloTM assay indirectly measuring 2-deoxy-d-glucose uptake in SKOV3, COS-7 or MCF-7 cells. The inhibitory effect on cancer cell growth was also determined in SKOV3 and MCF-7 cells, and #12 exhibited the best growth inhibitory effect equivalent to a known GLUT1 inhibitor WZB117. Although the anticancer effect of the identified potential GLUT1 inhibitors was moderate, they may enhance the activity of other anticancer drugs. Indeed, we found that #12 synergistically enhanced the anticancer activity of metformin in SKOV3 ovarian cancer cells.

mTOR Inhibitors Can Enhance the Anti-Tumor Effects of DNA Vaccines through Modulating Dendritic Cell Function in the Tumor Microenvironment.

The life span of dendritic cells (DCs) can become short following induced activation, which is associated with metabolic transition due to the regulation of mechanistic target of rapamycin (mTOR). The purpose of this study was to investigate the potential of inhibiting mTOR to modulate DC functions for elevating the anti-tumor effects of DNA vaccines. Therefore, the influences of various inhibitors of mTOR (mTORi) on the expressions of DC maturation markers, the abilities of antigen presenting and processing of BMM-derived DCs and the tumor killing effects of E7-specific CD8+ T lymphocytes activated by BMM-derived DCs were in vitro examined. The anti-tumor effects of connective tissue growth factor (CTGF)/E7 DNA vaccine and/or mTORi were also in vivo analyzed. In our study, suppressive effects of mTORi on the DC maturation markers expressed on BMMCs could be reversed. The mTORi-treated mature BMM-derived DCs tended to be non-apoptotic. These mTORi-treated BMM-derived DCs could have better antigen presenting and processing abilities. The E7-specific cytotoxic CD8+ T lymphocytes could have more potent tumoricidal activity following activation of mTORi-treated BMM-derived DCs. For tumor-bearing mice, those treated with CTGF/E7 DNA vaccine and mTORi indeed can have higher percentages of mature DCs in the TME, better disease control and longer survivals. Consequently, application of mTORi can be a pharmacological approach for temporally increasing life span, antigen presenting and antigen processing of DCs to strengthen the therapeutic outcome of cancer immunotherapy.

Change and predictors of symptom distress in breast cancer patients following the first 4 months after diagnosis.

BACKGROUND/PURPOSE: Breast cancer patients may encounter a wide range of physical and psychosocial distress symptoms during diagnosis, while awaiting treatment, and during treatment. This study of newly diagnosed breast cancer patients explores: (1) changes in symptom distress over 4 months; and (2) factors predicting changes in symptom distress. METHODS: A prospective longitudinal design was used to collect data from breast cancer patients in northern Taiwan. A set of questionnaires was used to measure anxiety, symptom distress, social support, and demographic and treatment-related characteristics. Repeated measures analysis of variance (RM-ANOVA) with least significant difference (LSD) was used to examine differences in symptom distress, state anxiety, and social-support levels across four time-points. Generalized estimating equation (GEE) is used to determine predictors for the change in symptom distress. RESULTS: Participants showed mild overall symptom distress during treatment that increased from cancer diagnosis to treatment phases, with a peak at 4 months after diagnosis. Insomnia was the most commonly identified distressful symptom over time. Changes in overall symptom distress were significantly predicted by state anxiety, health professional support, and time since cancer diagnosis. CONCLUSION: Change in symptom distress following the first 4 months after diagnosis was predicted by state anxiety, health professional support, and time. Patients should receive social support and be trained in problem-solving skills to relieve distressful symptoms from diagnosis through treatment.

Changes and predictors of unmet supportive care needs in Taiwanese women with newly diagnosed breast cancer.

PURPOSE/OBJECTIVES: To investigate changes in unmet supportive care needs and factors affecting those needs in Taiwanese women with newly diagnosed breast cancer. DESIGN: Prospective longitudinal survey. SETTING: Two general surgery outpatient departments at a large medical center in northern Taiwan. SAMPLE: 124 women with newly diagnosed breast cancer. METHODS: Needs were assessed with the Supportive Care Needs Survey-Short Form at diagnosis (T1) and one month (T2), two months (T3), and three months (T4) after diagnosis. MAIN RESEARCH VARIABLES: Supportive care needs. FINDINGS: Women had moderate-to-high levels of unmet needs, with the highest being in the health system and information domain at each time point. Levels in the domains of psychological, health system and information, and sexuality needs were higher (p < 0.001) at T1 than at T2, T3, and T4. However, levels of unmet physical and daily living needs increased significantly over time (p < 0.001). Unmet supportive care needs were significantly predicted by younger age and higher levels of education, symptom distress, trait anxiety, state anxiety, and time since diagnosis. CONCLUSIONS: Supportive care needs changed significantly over time and were predicted by personal characteristics, as well as physical and emotional factors. IMPLICATIONS FOR NURSING: Oncology nurses should assess the needs of patients with breast cancer and provide them with individualized, culturally sensitive informational, social, and emotional support from breast cancer diagnosis through the first four months of treatment.