ONC212, alone or in synergistic conjunction with Navitoclax (ABT-263), promotes cancer cell apoptosis via unconventional mitochondrial-independent caspase-3 activation.

Mitochondria-targeting agents, known as mitocans, are emerging as potent cancer therapeutics due to pronounced metabolic and apoptotic adaptations in the mitochondria of cancer cells. ONC212, an imipridone-family compound initially identified as a ClpP agonist, is currently under investigation as a potential mitocan with demonstrated preclinical efficacy against multiple malignancies. Despite this efficacy, the molecular mechanism underlying the cell death induced by ONC212 remains unclear. This study systematically investigates the mitochondrial involvement and signaling cascades associated with ONC212-induced cell death, utilizing HeLa and A549 cancer cells. Treated cancer cells exhibited characteristic apoptotic features, such as annexin-V positivity and caspase-3 activation; however, these occurred independently of typical mitochondrial events like membrane potential loss (ΔΨm) and cytochrome c release, as well as caspase-8 activation associated with the extrinsic pathway. Additionally, ONC212 treatment increased the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL, which impeded apoptosis, as the overexpression of Bcl-2-GFP and Bcl-xL-GFP significantly reduced ONC212-mediated cell death. Furthermore, combining a sub-lethal dose of the Bcl-2/Bcl-xL inhibitor Navitoclax with ONC212 markedly augmented caspase-3 activation and cell death, still without any notable ΔΨm loss or cytochrome c release. Moreover, inhibition of caspase-9 activity unexpectedly augmented, rather than attenuated, caspase-3 activation and the subsequent cell death. Collectively, our research identifies ONC212 as an atypical mitochondrial-independent, yet Bcl-2/Bcl-xL-inhibitable, caspase-3-mediated apoptotic cell death inducer, highlighting its potential for combination therapies in tumors with defective mitochondrial apoptotic signaling.

Alarming Trend in Under-Five Indian Children's Exposure to Indoor Tobacco Smoke.

BACKGROUND AND AIM: Children who are exposed to tobacco smoke (ETS) are at risk for a variety of health issues. There are enough legislative provisions in Indian law to safeguard children from ETS in outdoor settings, but no such specific rules exist to shield them from exposure indoors. This study aimed to examine the trend in under-five children's exposure to indoor tobacco smoke over the course of a decade (from 2005 to 2016) in India. MATERIALS AND METHODS: Data from the National Family and Health Survey (NFHS) for the years 2005-2006 (NFHS-3) and 2015-2016 (NFHS-4) on under-five children have been taken into consideration in cross-sectional analyses of the Demographic and Health Survey on India. Based on different sociodemographic factors, the propensity of indoor ETS among Indian children has been estimated and compared using both bivariate and multivariate logistic regression models. RESULTS: The prevalence of indoor ETS among Indian children under the age of five has greatly risen over the past decade, rising from 4.12% to 52.70%. According to the findings, there has been a noticeable increase in every group of kids, regardless of their age, place of residence, geographic location, socioeconomic status, and literacy level of their mothers. CONCLUSION: In India, the incidence of indoor ETS among children under five has risen by 13 times in the last 10 years, endangering the country. As a result, the Indian government must prepare to take legislative action to safeguard children by passing laws that forbid smoking inside.