STAT3 inhibition with Galiellalactone effectively targets the prostate cancer stem-like cell population."

Cancer stem cells (CSCs) are a small subpopulation of quiescent cells with the potential to differentiate into tumor cells. CSCs are involved in tumor initiation and progression and contribute to treatment failure through their intrinsic resistance to chemo- or radiotherapy, thus representing a substantial concern for cancer treatment. Prostate CSCs’ activity has been shown to be regulated by the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3). Here we investigated the effect of galiellalactone (GL), a direct STAT3 inhibitor, on CSCs derived from prostate cancer patients, on docetaxel-resistant spheres with stem cell characteristics, on CSCs obtained from the DU145 cell line in vitro and on DU145 tumors in vivo. We found that GL significantly reduced the viability of docetaxel-resistant and patient-derived spheres. Moreover, CSCs isolated from DU145 cells were sensitive to low concentrations of GL, and the treatment with GL suppressed their viability and their ability to form colonies and spheres. STAT3 inhibition down regulated transcriptional targets of STAT3 in these cells, indicating STAT3 activity in CSCs. Our results indicate that GL can target the prostate stem cell niche in patient-derived cells, in docetaxel-resistant spheres and in an in vitro model. We conclude that GL represents a promising therapeutic approach for prostate cancer patients, as it reduces the viability of prostate cancer-therapy-resistant cells in both CSCs and non-CSC populations

Global burden of disease due to smokeless tobacco consumption in adults: an updated analysis of data from 127 countries

BACKGROUND: Smokeless tobacco (ST) is consumed by more than 300 million people worldwide. The distribution, determinants and health risks of ST differ from that of smoking; hence, there is a need to highlight its distinct health impact. We present the latest estimates of the global burden of disease due to ST use. METHODS: The ST-related disease burden was estimated for all countries reporting its use among adults. Using systematic searches, we first identified country-specific prevalence of ST use in men and women. We then revised our previously published disease risk estimates for oral, pharyngeal and oesophageal cancers and cardiovascular diseases by updating our systematic reviews and meta-analyses of observational studies. The updated country-specific prevalence of ST and disease risk estimates, including data up to 2019, allowed us to revise the population attributable fraction (PAF) for ST for each country. Finally, we estimated the disease burden attributable to ST for each country as a proportion of the DALYs lost and deaths reported in the 2017 Global Burden of Disease study. RESULTS: ST use in adults was reported in 127 countries; the highest rates of consumption were in South and Southeast Asia. The risk estimates for cancers were also highest in this region. In 2017, at least 2.5 million DALYs and 90,791 lives were lost across the globe due to oral, pharyngeal and oesophageal cancers that can be attributed to ST. Based on risk estimates obtained from the INTERHEART study, over 6 million DALYs and 258,006 lives were lost from ischaemic heart disease that can be attributed to ST. Three-quarters of the ST-related disease burden was among men. Geographically, > 85% of the ST-related burden was in South and Southeast Asia, India accounting for 70%, Pakistan for 7% and Bangladesh for 5% DALYs lost. CONCLUSIONS: ST is used across the globe and poses a major public health threat predominantly in South and Southeast Asia. While our disease risk estimates are based on a limited evidence of modest quality, the likely ST-related disease burden is substantial. In high-burden countries, ST use needs to be regulated through comprehensive implementation of the World Health Organization Framework Convention for Tobacco Control