“(Not) All (Dead) Things Share the Same Breath”: Identification of Cell Death Mechanisms in Anticancer Therapy

Rello-Varona, Santiago; Herrero-Martín, David; López-Alemany, Roser; Muñoz-Pinedo, Cristina; Tirado, Óscar M.

doi:10.1158/0008-5472.can-14-3494

Cited by 28 publications

(23 citation statements)

References 34 publications

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“…To do so, a proper cell death mechanism characterization is paramount (37). In this sense, our results proved that the main mechanism involved in Dinaciclib killing is the mitochondrial apoptotic pathway (Figure 1D-E and Supplementary Figure 1B-E).…”

Section: Discussionsupporting

confidence: 60%

Bcl-x_L inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

Rello-Varona

Fuentes-Guirado

López-Alemany

et al. 2018

Preprint

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Soft-tissue sarcomas (STS) are an uncommon and heterogeneous group of malignancies that result in high mortality. Metastatic STS have very bad prognosis due to the lack of effective treatments. Dinaciclib is a model drug for the family of CDK inhibitors. Its main targets are cell cycle regulator CDK1 and protein synthesis controller CDK9. We present data supporting Dinaciclib ability to inactivate in vitro different STS models at nanomolar concentrations. Moreover, the different rhythms of cell death induction allow us to further study into the mechanism of action of the drug. Cell death was found to respond to the mitochondrial pathway of apoptosis. Anti-apoptotic Bcl-x L was identified as the key regulator of this process. Bcl-x L showed a slower decay curve after protein synthesis disruption that in tolerant cell lines was enough to delay apoptosis, as its action cannot be countered by the relative low levels of pro-apoptotic BH3 proteins BIM and PUMA. Combination of Dinaciclib with BH3-mimetics led to quick and massive apoptosis induction in vitro, but in vivo assessment was prevented due to liver toxicity. Additionally, Bcl-x L inhibitor A-1331852 also synergized with conventional chemotherapy drugs as Gemcitabine. Thus, Bcl-x L targeted therapy arises as a major opportunity to the treatment of STS.

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Section: Discussionsupporting

confidence: 60%

Bcl-x_L inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

Rello-Varona

Fuentes-Guirado

López-Alemany

et al. 2018

Preprint

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“…In contrast, a positive impact of p53 mutation on increased cell sensitivity to DNA damaging agents was detected by short-term assay in the NCI-60 cell line panel (30). Thus it is important to understand the mechanism by which cancer cells die (31), and its impact on the endpoint measured in the various assays.…”

Section: Focus Areas: Preclinical Radiobiological Assaysmentioning

confidence: 99%

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

Coleman

Higgins

Brown

et al. 2016

Clinical Cancer Research

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There is an urgent need to improve reproducibility and translatability of preclinical data in order to fully exploit opportunities for molecular therapeutics involving radiation and radio-chemotherapy. For in vitro the clonogenic assay remains the current state-of-the-art of preclinical assays, while newer moderate- and high-throughput assays offer the potential for rapid initial screening. Studies of radiation response modification by molecularly targeted agents can be improved using more physiologic 3D culture models. Elucidating effects on the cancer stem cells (CSC, and CSC-like) and developing biomarkers for defining targets and measuring responses are also important. In vivo studies are necessary to confirm in vitro findings, further define mechanism of action and address immune modulation and treatment-induced modification of the microenvironment. Newer in vivo models include genetically engineered and patient derived xenograft mouse models and spontaneously occurring cancers in domesticated animals. Selection of appropriate endpoints is important for in vivo studies, for example, regrowth delay measures bulk tumor killing while local tumor control assesses effects on CSC. The reliability of individual assays requires standardization of procedures and cross-laboratory validation. Radiation modifiers must be tested as part of clinical standard of care, which includes radio-chemotherapy for most tumors. Radiation models are compatible with, but also differ from those used for drug screening. Furthermore, the mechanism of a drug as a chemotherapy enhancer may be different than its interaction with radiation and/or radio-chemotherapy. This provides an opportunity to expand the use of molecular-targeted agents.

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“…Apoptotic cells decrease their volume while preserving the membrane integrity. On the other hand, during necrosis, the cells increase their volume until they release their content into extracellular space, which usually leads to inflammation (Nikoletopoulou et al 2013;Rello-Varona et al 2015). Therefore, the knowledge of the type of cells' death after the exposure to the tested compounds is essential to estimate their influence on a human organism and such information can determine the future applications of QDs.…”

Section: Introductionmentioning

confidence: 99%

Comparative studies of biological activity of cadmium-based quantum dots with different surface modifications

et al. 2018

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This paper presents a modification of the surface of CdS/ZnS and CdSe x S 1−x /ZnS quantum dots (QDs) with 3-mercaptopropionic and 6-mercaptohexanoic acid. The obtained QDs were characterized using TEM, DLS, UV-Vis, and fluorescence spectroscopy. Flow cytometry was applied to evaluate the cytotoxicity of QDs and examine the type of death caused by the tested nanoparticles. In addition, the generation of reactive oxygen species after incubation of the tested cells with CdSe x S 1−x / ZnS-MPA and CdSe x S 1−x /ZnS-MHA QDs was evaluated. The study was conducted on three cell lines: adherent (A549 and MRC-5) and suspension ones (K562). The conducted research demonstrated that the tested nanoparticles exhibit concentration-dependent toxicity. It was observed that the surface modification influences the toxicity level of the examined QDs, and modification of their surface with the use of the ligand of longer carbon chain (MHA) reduces the toxicity in comparison with QDs-MPA. It was also found that all tested QDs caused the death of cells in the course of necrosis. Based on obtained results, it was concluded that the cytotoxicity of QDs is to a large extent related to reactive oxygen species (ROS) generation.

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“(Not) All (Dead) Things Share the Same Breath”: Identification of Cell Death Mechanisms in Anticancer Therapy

Cited by 28 publications

References 34 publications

Bcl-x_L inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

Bcl-x_L inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

Comparative studies of biological activity of cadmium-based quantum dots with different surface modifications

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“(Not) All (Dead) Things Share the Same Breath”: Identification of Cell Death Mechanisms in Anticancer Therapy

Cited by 28 publications

References 34 publications

Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials

Comparative studies of biological activity of cadmium-based quantum dots with different surface modifications

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Product

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Bcl-x_L inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

Bcl-x_L inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas