The antipsychotic drug chlorpromazine enhances the cytotoxic effect of tamoxifen in tamoxifen-sensitive and tamoxifen-resistant human breast cancer cells

Yde, Christina Westmose; Clausen, Mathias P.; Bennetzen, Martin V.; Lykkesfeldt, Annè E.; Mouritsen, Ole G.; Guerra, Bárbara

doi:10.1097/cad.0b013e32832ec041

Cited by 55 publications

(38 citation statements)

References 38 publications

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“…Recently, Yde et al . corroborated this observation by showing that chlorpromazine enhances the cytotoxic effect of tamoxifen in tamoxifen-resistant human breast cancer cells [42]. The beneficial effect has also been found in colorectal cancer [43].…”

Section: Discussionmentioning

confidence: 76%

New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells

et al. 2016

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Drug resistance is an important open problem in cancer treatment. In recent years, the heat shock protein HSP27 (HSPB1) was identified as a key player driving resistance development. HSP27 is overexpressed in many cancer types and influences cellular processes such as apoptosis, DNA repair, recombination, and formation of metastases. As a result cancer cells are able to suppress apoptosis and develop resistance to cytostatic drugs. To identify HSP27 inhibitors we follow a novel computational drug repositioning approach. We exploit a similarity between a predicted HSP27 binding site to a viral thymidine kinase to generate lead inhibitors for HSP27. Six of these leads were verified experimentally. They bind HSP27 and down-regulate its chaperone activity. Most importantly, all six compounds inhibit development of drug resistance in cellular assays. One of the leads – chlorpromazine – is an antipsychotic, which has a positive effect on survival time in human breast cancer. In summary, we make two important contributions: First, we put forward six novel leads, which inhibit HSP27 and tackle drug resistance. Second, we demonstrate the power of computational drug repositioning.

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Section: Discussionmentioning

confidence: 76%

New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells

et al. 2016

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“…Over the last more than 50 years it has become clear that many different neurotransmitter systems are implicated in the neuropathology of schizophrenia. This started with the dopamine hypothesis (e.g., Carlsson and Lindqvist, 1963) and the implication of serotonin (e.g. Woolley and Shaw, 1954) in the early 50 and 60 s, moving on to the glutamate hypothesis (e.g., Javitt et al, 1994; Javitt, 2004) followed by an implication of GABAergic circuits (e.g., Perry et al, 1979; Rosso et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Multifactorial Modeling of Impairment of Evoked Gamma Range Oscillations in Schizophrenia

Metzner

Schweikard²,

Zurowski

2016

Front. Comput. Neurosci.

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Despite a significant increase in efforts to identify biomarkers and endophenotypic measures of psychiatric illnesses, only a very limited amount of computational models of these markers and measures has been implemented so far. Moreover, existing computational models dealing with biomarkers typically only examine one possible mechanism in isolation, disregarding the possibility that other combinations of model parameters might produce the same network behavior (what has been termed “multifactoriality”). In this study we describe a step toward a computational instantiation of an endophenotypic finding for schizophrenia, namely the impairment of evoked auditory gamma and beta oscillations in schizophrenia. We explore the multifactorial nature of this impairment using an established model of primary auditory cortex, by performing an extensive search of the parameter space. We find that single network parameters contain only little information about whether the network will show impaired gamma entrainment and that different regions in the parameter space yield similar network level oscillation abnormalities. These regions in the parameter space, however, show strong differences in the underlying network dynamics. To sum up, we present a first step toward an in silico instantiation of an important biomarker of schizophrenia, which has great potential for the identification and study of disease mechanisms and for understanding of existing treatments and development of novel ones.

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“…Tumors display resistance to anticancer therapy by (a) molecular alteration in the transmembrane drug transport, (b) increase in the repair and detoxification pathways and lastly (c) by molecular alteration of genes resulting in failure in pro-apoptotic response. Currently, the probability for long-term survival in patients may be improved by combining anticancer chemotherapy with tocotrienols (Yap et al 2010;Yde et al 2009;Leonessa et al 1994).…”

Section: In Vitro Studiesmentioning

confidence: 99%

Tocotrienols and breast cancer: the evidence to date

et al. 2011

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Breast cancer is the second most frequent cancer affecting women worldwide after lung cancer. The toxicity factor associated with synthetic drugs has turned the attention toward natural compounds as the primary focus of interest as anticancer agents. Vitamin E derivatives consisting of the well-established tocopherols and their analogs namely tocotrienols have been extensively studied due to their remarkable biological properties. While tocopherols have failed to offer protection, tocotrienols, in particular, a-, d-, and c-tocotrienols alone and in combination have demonstrated anticancer properties. The discovery of the antiangiogenic, antiproliferative, and apoptotic effects of tocotrienols, as well as their role as an inducer of immunological functions, not only reveals a new horizon as a potent antitumor agent but also reinforces the notion that tocotrienols are indeed more than antioxidants. On the basis of a transcriptomic platform, we have recently demonstrated a novel mechanism for tocotrienol activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicate a high affinity of specific forms of tocotrienols for ERb, but not for ERa. Moreover, we have demonstrated that specific tocotrienols increase ERb translocation into the nucleus which, in turn, activates the expression of estrogenresponsive genes (MIC-1, EGR-1 and Cathepsin D) in breast cancer cells only expressing ERb cells (MDA-MB-231) and in cells expressing both ER isoforms (MCF-7). The binding of specific tocotrienol forms to ERb is associated with the alteration of cell morphology, caspase-3 activation, DNA fragmentation, and apoptosis. Furthermore, a recently concluded clinical trial seems to suggest that tocotrienols in combination with tamoxifen may have the potential to extend breast cancer-specific survival.

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The antipsychotic drug chlorpromazine enhances the cytotoxic effect of tamoxifen in tamoxifen-sensitive and tamoxifen-resistant human breast cancer cells

Cited by 55 publications

References 38 publications

New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells

New HSP27 inhibitors efficiently suppress drug resistance development in cancer cells

Multifactorial Modeling of Impairment of Evoked Gamma Range Oscillations in Schizophrenia

Tocotrienols and breast cancer: the evidence to date

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