Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines

Recent data have demonstrated that the anti-oestrogen tamoxifen (TAM) is able to facilitate apoptosis in cancer cells not expressing oestrogen receptor (ER). In an attempt to identify the biochemical pathway for this phenomenon, we investigated the role of TAM as an oxidative stress agent. In two ER-negative human cancer cell lines, namely T-leukaemic Jurkat and ovarian A2780 cancer cells, we have demonstrated that TAM is able to generate oxidative stress, thereby causing thiol depletion and activation of the transcriptional factor NF-κB. As described for other oxidative agents, TAM was able to induce either cell proliferation or apoptosis depending on the dose. When used at the lowest dose tested (0.1 μM), a slight proliferative effect of TAM was noticed in terms of cell counts and DNA synthesis rate, whereas at higher doses (10 μM) a consistent occurrence of apoptosis was detected. Importantly, the induction of apoptosis by TAM is not linked to down-regulation or functional inactivation by phosphorylation of the antiapoptotic bcl-2 protein. © 1999 Cancer Research Campaig

Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells

Introduction: The HIV protease inhibitor nelfinavir is currently under investigation as a new anti-cancer drug. Several studies have shown that nelfinavir induces cell cycle arrest, endoplasmic reticulum stress, autophagy, and apoptosis in cancer cells. In the present article, the effect of nelfinavir on human breast cancer cells is examined and potential combination treatments are investigated. Methods: The effects of nelfinavir and tamoxifen on the human breast cancer cell lines MCF7, T47 D, MDA-MB-453, and MDA-MB-435 were tested by analysing their influence on cell viability (via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay), apoptosis (annexin binding, poly(ADP-ribose) polymerase cleavage), autophagy (autophagy marker light chain 3B expression), endoplasmic reticulum stress (binding protein and activating transcription factor 3 expression), and the occurrence of oxidative stress (intracellular glutathione level). Results: Nelfinavir induced apoptosis in all four breast cancer cell lines tested, although the extent of autophagy and endoplasmic reticulum stress varied among the cell lines. The concentration of nelfinavir needed for an efficient induction of apoptosis in breast cancer cells could be reduced from 15 mu g/ml to 6 mu g/ml when combined with tamoxifen. At a concentration of 6 mu g/ml, tamoxifen substantially enhanced the endoplasmic reticulum stress reaction in those cell lines that responded to nelfinavir with binding protein (BiP) upregulation (MCF7, T47D), and enhanced autophagy in cell lines that responded to nelfinavir treatment with autophagy marker light chain 3B upregulation (MDA-MB-453). Although tamoxifen has been described to be able to induce oxidative stress at concentrations similar to those applied in this study (6 mu g/ml), we observed that nelfinavir but not tamoxifen reduced the intracellular glutathione level of breast cancer cells within hours of application by up to 32%, suggesting the induction of oxidative stress was an early event and an additional cause of the apoptosis induced by nelfinavir. Conclusions: The results demonstrate that nelfinavir may be an effective drug against breast cancer and could be combined with tamoxifen to enhance its efficacy against breast cancer cells. Moreover, the cytotoxic effect of a tamoxifen and nelfinavir combination was independent of the oestrogen receptor status of the analysed breast cancer cells, suggesting a potential benefit of a combination of these two drugs even in patients with no hormone-responsive tumours. We therefore recommend that clinical studies on nelfinavir with breast cancer patients should include this drug combination to analyse the therapeutic efficacy as well as the safety and tolerability of this potential treatment option

Diverse values of nature for sustainability

Data availability: All the data are freely available online. The supplementary information provides links to Zenodo with specific DOIs where the data are stored for free use.Supplementary information is available online at https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-023-06406-9/MediaObjects/41586_2023_6406_MOESM1_ESM.docx . The Supplementary Information includes three parts. Part A explains how the paper is associated with the IPBES Values Assessment. Part B provides details about each of the 29 review protocols. Part C offers information about the case study of Chilika Lagoon, India, that is used in the main paper.Copyright © The Author(s) 2023. Twenty-five years since foundational publications on valuing ecosystem services for human well-being1,2, addressing the global biodiversity crisis3 still implies confronting barriers to incorporating nature’s diverse values into decision-making. These barriers include powerful interests supported by current norms and legal rules such as property rights, which determine whose values and which values of nature are acted on. A better understanding of how and why nature is (under)valued is more urgent than ever4. Notwithstanding agreements to incorporate nature’s values into actions, including the Kunming-Montreal Global Biodiversity Framework (GBF)5 and the UN Sustainable Development Goals6, predominant environmental and development policies still prioritize a subset of values, particularly those linked to markets, and ignore other ways people relate to and benefit from nature7. Arguably, a ‘values crisis’ underpins the intertwined crises of biodiversity loss and climate change8, pandemic emergence9 and socio-environmental injustices10. On the basis of more than 50,000 scientific publications, policy documents and Indigenous and local knowledge sources, the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) assessed knowledge on nature’s diverse values and valuation methods to gain insights into their role in policymaking and fuller integration into decisions7,11. Applying this evidence, combinations of values-centred approaches are proposed to improve valuation and address barriers to uptake, ultimately leveraging transformative changes towards more just (that is, fair treatment of people and nature, including inter- and intragenerational equity) and sustainable futures.We received no specific funding for this work; all authors involved in IPBES do so on a voluntary basis. The IPBES Values Assessment was made possible thanks to many generous contributions, including non-earmarked contributions to the IPBES trust fund from governments. All donors are listed on the IPBES website www.ipbes.net/donors. U.P. acknowledges BC3’s Maria de Maeztu excellence accreditation 2023–2026 (reference no. CEX2021-001201-M) provided by grant no. MCIN/AEI/10.13039/501100011033

Meta-analysis of nature conservation values in Asia & Oceania: Data heterogeneity and benefit transfer issues

We conduct a meta-analysis (MA) of around 100 studies valuing nature conservation in Asia and Oceania. Dividing our dataset into two levels of heterogeneity in terms of good characteristics (endangered species vs. nature conservation more generally) and valuation methods, we show that the degree of regularity and conformity with theory and empirical expectations is higher for the more homogenous dataset of contingent valuation of endangered species. For example, we find that willingness to pay (WTP) for preservation of mammals tends to be higher than other species and that WTP for species preservation increases with income. Increasing the degree of heterogeneity in the valuation data, however, preserves much of the regularity, and the explanatory power of some of our models is in the range of other MA studies of goods typically assumed to be more homogenous (such as water quality). Subjecting our best MA models to a simple test forecasting values for out-of-sample observations, shows median (mean) forecasting errors of 24 (46) percent for endangered species and 46 (89) percent for nature conservation more generally, approaching levels that may be acceptable in benefit transfer for policy use. We recommend that the most prudent MA practice is to control for heterogeneity in regressions and sensitivity analysis, rather than to limit datasets by non-transparent criteria to a level of heterogeneity deemed acceptable to the individual analyst. However, the trade-off will always be present and the issue of acceptable level of heterogeneity in MA is far from settle