Hyperthermia has been revived as a promising approach for cancer treatment. To understand the underlying mechanisms of hyperthermic killing of cancer cells, we examined the cytotoxic effects of hyperthermia on various skin cancer cell lines using cell viability, morphological analyses, and caspase activation assays. Hyperthermia induced cytotoxicity in a time- and temperature-dependent manner. At middle dose/time combinations, heat-induced apoptosis, whereas at higher doses, necrosis was the mechanism of cell death. To investigate the mechanisms of hyperthermia-induced apoptosis, we examined the activation of extrinsic (Caspase 8) and intrinsic (Caspase 9) apoptotic pathways. Hyperthermia did not activate Caspases 8 or 9, but did activate Caspase 3/7, suggesting a non-conventional apoptotic pathway. Last, analysis of Grp78 expression and Caspase 12 or 4 activation indicated that hyperthermia induced endoplasmic reticulum-mediated apoptosis. Thus, hyperthermia induced apoptosis in two types of skin cancer cells through endoplasmic reticulum-mediated apoptosis and not through the classical intrinsic or extrinsic apoptosis pathways. Hyperthermia may be a promising treatment for basal cell carcinoma and melanoma, bypassing the antiapoptotic defenses concentrated in the intrinsic and extrinsic apoptosis pathways. These results also raise the possibility that heat may be combined with other approaches for induction of apoptosis to achieve synergistic killing of skin cancers.
Objectives: We conducted a prospective analysis of the relation between breast size measured by self-reported bra cup size and breast cancer risk among a cohort of premenopausal women. Design: Prospective cohort study Setting: The Nurses' Health Study II is an ongoing, prospective cohort of 116,671 American female registered nurses. The study was initiated in 1989 and enrolled women between 25 -42 years of age living within 14 states in the U.S. Participants: Bra cup size and breast cancer risk was assessed among 88,787 premenopausal women aged 29 to 47 in 1993. Bra cup size at age 20 was assessed by self-report in 1993. Women were excluded if at baseline they were postmenopausal, reported previous cancer, or did not report bra cup size. Censoring occurred if a women experienced breast cancer, reached menopause or died. Main Outcome Measures: New cases of invasive breast cancer were self-reported and confirmed by review of pathology reports. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with a Cox proportional hazards model adjusting for potential risk factors for breast cancer. All statistical tests were twosided. Results: During 621,097 total years of follow-up, 893 women developed incident invasive breast cancer. For women with a body mass index (BMI) below 25, those with a bra cup size of "B" (covariate adjusted HR=1.22, 95% CI 1.00-1.49) and "D or larger" (covariate adjusted HR=1.77, 95% CI 1.13-2.77) had an increased risk of breast cancer relative to "A or smaller" (Ptrend = 0.01). There was no important association among women with a BMI of 25 or higher. Stratifying by BMI at age 18 using a cut point of 21 gave similar results. Conclusion: Larger bra cup size at a younger age is associated with an increased risk of premenopausal breast cancer, though this association is limited to leaner women.
PurposeTreating disease with hyperthermia dates back to 3000 BC when Egyptian physicians explored the therapeutic benefits of heating diseased tissues. There has been renewed interest in using hyperthermia to treat cancer over the last 30 years. Hyperthermia as an adjuvant anti-cancer therapy has demonstrated improved clinical outcomes and increased response rates when combined with conventional treatments of tumors. This project investigated the molecular mechanisms of hyperthermia induced cell death in human melanoma cells in-vitro. Data from these experiments may help in the generation of new treatment modalities for skin cancer.MethodsCopper blocks inside incubators delivered a uniform and reproducible hyperthermia treatment to human melanoma cells grown in 96 well plates. A sophisticated measurement device with fast-response thermocouples in a 96 well format measured the thermal dose delivered to the cells. The human melanoma cells received hyperthermia treatments ranging from 15-120 mins at 41, 45 and 48°C. The treated cells were analyzed for overall viability, the mechanism of cell death, and whether there was a relationship between the thermal-doses delivered and the cell death pathway induced. Cell viability was measured in each well post treatment using an MTS based assay (CellTiter 96 Aqueous One Promega). The activity of apoptosis specific caspases 3 and 7 were measured using a homogeneous luminescent assay (Caspase-Glo3/7 Promega). Nuclear condensation and fragmentation was assessed in an eloquent microscopic approach using a modified ethidium bromide and acridine orange staining assay (EB/AO) in a 96 well format.ResultsWe consistently demonstrated that hyperthermia decreased cell viability in human melanoma cells in-vitro, and that the diminished cell viability was proportional the thermal dose delivered. Hyperthermia also induced activation of caspase 3 and 7, and increased the population of cells with condensed or fragmented nuclei. This data suggest that hyperthermia induced apoptosis in human melanoma cells.ConclusionsHyperthermia induces dose-dependent apoptosis in human melanoma cells. Further elucidation of these pathways will help in the design and discovery of novel methods for treating skin cancers.
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