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Salicylic acid and Hsp70: partners for inducing apoptosis in breast cancer cells?

  • Authors: Ferreira, Eloise
  • Date: 2011-05-16T07:46:23Z
  • Subjects: Salicylic acid , Heat shock proteins , Cancer cells , Apoptosis , Breast cancer treatment
  • Type: Thesis
  • Identifier: uj:7073 , http://hdl.handle.net/10210/3636
  • Description: M.Sc. , Breast cancer is the most commonly diagnosed cancer and cause of death in women world wide as well as in South Africa. Cancer is characterized by over-proliferation of cells or the inhibition of programmed cell death known as apoptosis, a well coordinated process that results in the activation of several proteases and other hydrolytic enzymes. Apoptosis is regulated by enhancers and inhibitors, such as heat shock proteins (Hsps) that modulate the apoptotic process according to the demands of specific cells. Hsps can regulate the release of pro-apoptotic factors from the mitochondria as well as inhibit key steps in the apoptotic cascade such as activation of caspases. The Hsp70 family constitutes the most conserved and best studied class of Hsps and the stress-induced Hsp70 also blocks the apoptotic pathway at different levels. Hsp70 is furthermore overexpressed in several tumor cells and can effectively inhibit cell death induced by a wide range of stimuli including several cancer related stresses such as hyperthermia, chemotherapeutic agents and nonsteroidal anti-inflammatory drugs (NSAIDs) i.a. aspirin (acetylated salicylic acid) In addition to their potent analgesic, antipyretic and anti-inflammatory activity, NSAIDs can inhibit cell proliferation and induce apoptosis in many cancer cell lines. However, NSAIDs can also lower the temperature threshold for Hsp70 induction and induce a transcriptionally inert intermediate of Hsp70 that can be converted to a transcriptionally active state by a subsequent exposure to heat shock. This suggests that NSAIDs act differently under heat stress, possibly increasing cellular protection through the heat shock response in cancer cells with already elevated levels of Hsps. It is therefore hypothesized that the synergistic use of heat shock with salicylic acid (SA) treatment will increase Hsp70 expression and protein accumulation and further enhance the resistance of breast cancer cells to apoptosis. The effects of SA on its own or in combination with HS on the viability of MCF-7 breast cancer cells as well as Hsp70 protein levels and gene expression were therefore investigated. SA treatments were found to induce cell death in a dose-dependent manner with the most significant decrease in viability observed after treatment with 20 mM SA.
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Investigating the effects of in vitro photodynamic treatment with two metallo-phthalocyanines in MCF-7 breast cancer cells

  • Authors: Horne, Tamarisk Kerry
  • Date: 2009-11-23T07:00:34Z
  • Subjects: Breast cancer treatment , Photochemotherapy , Phthalocyanines , Cancer cells , Cell death , Photosensitizing compounds
  • Type: Thesis
  • Identifier: uj:6619 , http://hdl.handle.net/10210/3011
  • Description: M.Sc. , Established therapies currently in use for the treatment of breast cancer are high risk, since their employment harbors multiple undesirable and detrimental side effects. In many cases these are associated with poor therapeutic outcome managing only to briefly extend patient lifespan. As a result, many newly designed treatments have surfaced that aim to effectively remove cancerous tissue and improve survival rates while minimizing the aggressive onsets to the patient. Photodynamic Therapy (PDT) has, for a long time, been targeted as a combatant for cancer. Its therapeutic mechanism is based on the tumor-specific intracellular localization of a photosynthetic compound, i.e: photosensitizer, prior to its irradiation-mediated excitation thereby generating high levels of reactive oxygen species (ROS). At the molecular level, this causes irreversible photodamage to vital intracellular targets resulting in cell death. The plasma membrane-, mitochondrial-, lysosomal-, and endoplasmic reticulum systems are all prime targets of PDT and vary in susceptibility depending on both the type of cancer being treated and the photosensitizer administered. Newly designed photosensitizers are governed by their enhanced structural properties to localize and therefore target certain areas of a cell. Since each cancer type has a unique set of susceptible and resistant characteristics, knowledge of each new photosensitizers’ range, efficiency, and mechanism of cell death is required. This enables pairing of these drugs to appropriate cancer types for maximal PDT effect. Here, two newly designed metallo-phthalocyanine photosensitizers, AlPcSmix and GePcSmix, were analyzed for their photodynamic effect on the estrogen-positive, breast cancer cell line, MCF-7. Being one of the most reliable cell lines, it is a prominent research model because it mimics the problems encountered with tumor resistance to therapy induced cell death via pathway restrictions. Photosensitizer administration and excitation by light irradiation to this cell culture system was therefore referred to as in vitro Photodynamic Treatment (in vitro PDT) and not Therapy. ii Initial dosage and time responsive studies confirmed that 35 μM AlPcSmix and 115 μM GePcSmix both excited using 15 J/cm2 at 680 nm proved most effective in reducing viability, whilst individually contributing little adverse influence to cellular homeostasis. Using these dosages, in vitro PDT analysis on several cellular parameters indicated a complex mode of cell death was induced. Morphology revealed typical markers consistent with apoptotic, autophagic and necrotic cell death while variations in proliferation and cytotoxicity levels were inconsistent with stress responses observed. This correlated with the detection for four common apoptotic markers which also revealed discrepancies within the death pathway as possible mutational deficiencies may have rendered MCF-7 cellular systems incomplete. Taken together, the wide range of cellular parameters studied suggests cells undergo a mixture of death modes interchanging via a complex system of molecular switches over time that concludes in secondary necrosis. This was attributed to the assortment of sulphonated phthalocyanine species enabling a broad intracellular distribution range coupled with the non-specific targeting action typical of the ROS generated, in addition to the absence of a phagocytic conclusion to the death process. In vitro PDT with AlPcSmix was shown to harbor a greater toxicity to GePcSmix as cells completed the death response within a shorter time period however, both promoted MCF-7 population cell death sufficient enough to warrant further study for their use as potential agents in the PDT of breast cancer.
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Salicylic acid mediated potentiation of Hsp70 abates apoptosis resistance in breast cancer cells

  • Authors: Jackson, Ashleigh
  • Date: 2010-04-19T07:54:34Z
  • Subjects: Cancer cells , Apoptosis , Heat shock proteins , Salicylic acid , Breast cancer treatment
  • Type: Thesis
  • Identifier: uj:6793 , http://hdl.handle.net/10210/3222
  • Description: M.Sc. , Heat shock (HS) proteins and HS transcription factors (HSFs) have been coined as the ‘Achilles Heel’ for cancer therapy, since they have been found to be overexpressed in cancer cells and are required for cell survival during tumour progression and metastasis. Hsp70 and other members of the Hsp family have been shown to inhibit apoptosis at several different stages, contributing to resistance to chemotherapy. NSAIDs, like salicylates and aspirin, are used for the treatment and prevention of cancers such as breast cancer. SA has been shown to enhance HSF-DNA binding and results in the increased expression of heat-induced Hsp70 which is antiapoptotic. We hypothesise that SA treatment can result in the potentiation of Hsp70 in MCF-7 cells further increasing their resistance to apoptosis and thus the aim of this study was to investigate the dose-responsive effects of salicylic acid (SA) in the presence and absence of heat shock on components of the pro and antiapoptotic components of the apoptotic pathway. MCF-7 cells, which naturally overexpress Hsp70, were treated with several doses of SA in the presence and absence of a mild heat shock, followed by analysis of Hsp70 and several pro and antiapoptotic members of intrinsic and extrinsic apoptotic pathways, including Bcl-2, Bax, caspase 6 and 8, JNK, AIF and APAF-1. Induced Hsp70 accumulation by the SA treatments in the presence and absence of heat shock enhanced apoptosis in cells exposed to SA whereas higher concentrations of SA combination with heat shock induced necrosis and a decrease in Hsp70 accumulation in MCF-7 cells. Identification of the effects which specific concentrations of SA in the presence and absence of heat shock had on the apoptotic pathway constituents helped highlight potential pathways by which cell death could occur in MCF-7 cells through the downregulation of Hsp70. It is most likely that MCF-7 cell death is occurring due to the release of reactive oxygen species (ROS) which in turn lead to necrosis or death may be achieved via a cathepsin-B-mediated cell death pathway where both of these possibilities need to be further investigated.
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The efficacy of astragalus membranaceous tincture at maintaining the circulating leucocyte and absolute neutrophil counts of breast cancer patients undergoing chemotherapeutic treatment

  • Authors: Minnaar, Carrie-Anne
  • Date: 2010-04-08T08:36:54Z
  • Subjects: Breast cancer chemotherapy , Breast cancer treatment
  • Type: Thesis
  • Identifier: uj:6754 , http://hdl.handle.net/10210/3161
  • Description: M. Tech. , AIM: To determine the efficacy of Astragalus membranaceous tincture at maintaining the circulating white blood cell count (WBC) and absolute neutrophil count (ANC) of breast cancer patients receiving chemotherapy. METHODS: This is an open-label study with an active control group. Both the study and control group consisted of fifteen participants. The participants in the study group each received ten millilitres of Astragalus membranaceous 1:2 tincture daily for the duration of their course of chemotherapy. RESULTS: The overall decrease in the WBC and ANC in the control was 4.9 and 3.13 parts per billion per litre, respectively. The study group showed an overall decrease of 2.7 and 1.9 parts per billion per litre, respectively. The average overall reduction in chemotherapy dose was 4.79 percent in the study group and 20.21 percent in the control. In all of the analyses p > 0.05. The small sample size, poor patient compliance and skewed distribution of the variables hindered the reliability of the results. CONCLUSION: The positive effects observed in the study group cannot be extrapolated to the entire population, however further research is strongly motivated.
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Inorganic nanoparticles applied for active targeted photodynamic therapy of breast cancer

Hope and ways of coping after breast cancer

  • Authors: Rubin, Hayley Harriet
  • Date: 2008-11-12T08:47:53Z
  • Subjects: Breast cancer , Breast cancer treatment , Adjustment (Psychology) , Hope
  • Type: Thesis
  • Identifier: uj:14665 , http://hdl.handle.net/10210/1638
  • Description: M.A. , The aim of this study was to ascertain the coping methods of women in long term follow-up of breast cancer treatment. Furthermore, personality traits that deal with the spectrum of positive affectivity were introduced to determine whether these impact on women's appraisal of their situation and their subsequent choice of coping mechanism. Thus, a process approach to exploring coping strategies and a goal-attainment conceptualization of hope were used to determine whether hope is associated with coping appraisal in the long term follow-up of breast cancer treatment. Furthermore, high hope women were expected to use more problem focused coping methods and low hope women were expected to use more emotion focused coping skills. Women in cancer remission who attend yearly or six-monthly check-ups at the Johannesburg hospital were approached to complete the questionnaire and brief interview. Although the study did not confirm that low hope and high hope women use different kinds of coping strategies, the predicted relationship between hope and challenge appraisals was supported by significant correlations. However, it was found that hope may be analogous to positive affect, thus indicating the need for further validation of the Hope Scale. Finally, it was concluded that breast cancer need not be seen as a devitalising disease and that there are a variety of coping strategies which can be utilized to enhance patient's positive emotional state. The women in this study use the emotion focused coping skill of positive reappraisal which concentrates on the possibilities for mastery and growth that inhere in their long term follow-up treatment. Moreover, women are extremely positive and hopeful in their daily outlook and while this personality trait seems to suggest that denial is at play, it is more likely that women in long term remission have a strong belief in their own personal qualities and future. Women in this study choose to distance themselves from the implicit trauma of the threat of recurrence in favour of an active belief in their personal resilience to overcome any stressful event or outcome.
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