The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells.

Pharmacological induction of proteotoxic stress is rapidly emerging as a promising strategy for cancer cell-directed chemotherapeutic intervention. Here, we describe the identification of a novel drug-like heat shock response inducer for the therapeutic induction of proteotoxic stress targeting malignant human melanoma cells. Screening a focused library of compounds containing redox-directed electrophilic pharmacophores employing the Stress & Toxicity PathwayFinder(TM) PCR Array technology as a discovery tool, a drug-like triphenylmethane-derivative (aurin; 4-[bis(p-hydroxyphenyl)methylene]-2,5-cyclohexadien-1-one) was identified as an experimental cell stress modulator that causes (i) heat shock factor transcriptional activation, (ii) up-regulation of heat shock response gene expression (HSPA6, HSPA1A, DNAJB4, HMOX1), (iii) early unfolded protein response signaling (phospho-PERK, phospho-eIF2α, CHOP (CCAAT/enhancer-binding protein homologous protein)), (iv) proteasome impairment with increased protein-ubiquitination, and (v) oxidative stress with glutathione depletion. Fluorescence polarization-based experiments revealed that aurin displays activity as a geldanamycin-competitive Hsp90α-antagonist, a finding further substantiated by molecular docking and ATPase inhibition analysis. Aurin exposure caused caspase-dependent cell death in a panel of human malignant melanoma cells (A375, G361, LOX-IMVI) but not in non-malignant human skin cells (Hs27 fibroblasts, HaCaT keratinocytes, primary melanocytes) undergoing the aurin-induced heat shock response without impairment of viability. Aurin-induced melanoma cell apoptosis depends on Noxa up-regulation as confirmed by siRNA rescue experiments demonstrating that siPMAIP1-based target down-regulation suppresses aurin-induced cell death. Taken together, our data suggest feasibility of apoptotic elimination of malignant melanoma cells using the quinone methide-derived heat shock response inducer aurin.

Mammography Compliance for Arizona and New Mexico Hispanic and American Indian Women 2016-2018.

Hispanic and American Indian (AI) women experience lower breast cancer incidence than non-Hispanic White (NHW) women, but later-stage diagnoses and lower survival rates, suggesting issues with screening and healthcare access. Between 1999-2015, NHW breast cancer incidence decreased by 10% but increased by 8% for AI women. This study used 2016 and 2018 Behavioral Risk Factor Surveillance System data for Arizona and New Mexico to explore mammography screening. Analyses included Hispanic, AI, and NHW women aged ≥40 years (n = 12,830) to calculate age-specific compliance by race/ethnicity, logistic regression, and adjusted and sample-weighted evaluated associations between compliance and socio-economic covariates. In total, 75.1% of Hispanic women aged 50-74 reported mammography in the past two years (United States Preventive Services Task Force compliant) compared to 73.9% of NHW and 71.0% of AI women. Women who reported doctor visits in the past 12 months were likelier to comply than those without (AOR = 4.2 for Hispanic, 2.9 for AI, and 3.2 for NHW women). Reporting access to a personal doctor was related to compliance, except for AI women. While screening compliance was over 74%, visiting a healthcare provider in the past 12 months was essential. AI women reported issues that suggest unique challenges when deciding on mammography.