Daunorubicin can eliminate iPS-derived cancer stem cells via ICAD/CAD-independent DNA fragmentation

Aim: To identify a drug that can effectively eliminate these cancer stem cells (CSCs) and determine its mode of action.Methods: CSCs were obtained from mouse induced pluripotent stem cells (miPSCs) using cancer cell-conditioned media. Drug screening was performed on these cells or after transplantation into mice. Apoptosis was analyzed by flow cytometry and western blotting.Results: Drug screening studies showed that daunorubicin, a topoisomerase II inhibitor, is specifically cytotoxic to miPS-CSCs. Daunorubicin-induced apoptosis was found to be associated with p53 accumulation, activation of the caspase cascade, and oligonucleosomal DNA fragmentation. Treatment with the caspase inhibitor abolished daunorubicin-induced DNA fragmentation and was therefore considered to act downstream of caspase activation. This was also suppressed by treatment with a Ca2+-specific chelator, which suggested that CAD endonuclease does not contribute. Moreover, no obvious ICAD reduction/degradation was detected.Conclusion: Daunorubicin effectively eliminated CSCs, which are dependent on the p53/caspase signaling cascade. The current findings provided the basis for further studies on CSC-targeted drugs for the development of cancer treatment strategies

Effects of Noise-Induced Hearing Loss at Young Age on Voice Onset Time and Gap-in-Noise Representations in Adult Cat Primary Auditory Cortex

Here we show that mild hearing loss induced by noise exposure in early age causes a decrease in neural temporal resolution when measured in adulthood. We investigated the effect of this chronic hearing loss on the representation of a voice onset time (VOT) and a gap-duration continuum in primary auditory cortex (AI) in cats, which were exposed at the age of 6 weeks to a 120-dB SPL, 5-kHz 1/3 octave noise band for 2 h. The resulting hearing loss measured using auditory brainstem responses and cortical multiunit thresholds at 4–6 months of age was 20–40 dB between 1 and 32 kHz. Multiple single-unit activity was recorded in seven noise-exposed cats and nine control cats related to the presentation of a/ba/–/pa/ continuum in which VOT was varied in 5-ms step from 0 to 70 ms. We also obtained data for noise bursts with gaps, of duration equal to the VOT, embedded in noise 5 ms after the onset. Both stimuli were presented at 65 dB SPL. Minimum VOT and early-gap duration were defined as the lowest value in which an on-response, significantly above the spontaneous activity, to both the leading and trailing noise bursts or vowel was obtained. The mild chronic noise-induced hearing loss increased the minimum detectable VOT and gap duration by 10 ms. We also analyzed the maximum firing rate (FRmax) and the latency of the responses as a function of VOT and gap duration and found a significant reduction in the FRmax to the trailing noise burst for gap durations above 50 ms. This suggests that mild hearing loss acquired in early age may affect cortical temporal processing in adulthood