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Rationale: Cancer stem cells (CSCs) are known to cause tumor recurrence and drug resistance. The heat shock protein (HSP) system plays a major role in preserving expression and function of numerous oncoproteins, including those involved in the CSC activities. We explored novel anticancer drugs, especially those targeting HSP components required for the functional role of CSCs. Methods: Investigation of the role of the HSP system in CSCs and screening of a natural product chemical library were performed by utilizing cancer cell lines, primary cultures of patient-derived xenografts (PDXs), and their putative CSC subpopulations (i.e., those grown under sphere-forming conditions, stably transfected with reporter vectors carrying NANOG or POUSF1 promoters, or carrying high ALDH activity) in vitro and PDX and Kras G12D/+ -driven tumor models in vivo. Regulation of the HSP system was investigated by immunoprecipitation, drug affinity responsive target stability assay, binding experiments using ATP-agarose beads and biotinylated drug, and docking analysis. Results: The HSP system was activated in CSCs via transcriptional upregulation of the HSP system components, especially HSP70. Evodiamine (Evo) was identified to induce apoptosis in both CSC and bulk non-CSC populations in human lung, colon, and breast cancer cells and their sublines with chemoresistance. Evo administration decreased the multiplicity, volume, and load of lung tumors in Kras G12D/+ transgenic mice and the growth of cancer cell line- and PDX-derived tumors without detectable toxicity. Mechanistically, Evo disrupted the HSP system by binding the N-terminal ATP-binding pocket of HSP70 and causing its ubiquitin-mediated degradation. Conclusions: Our findings illustrate HSP70 as a potential target for eliminating CSCs and Evo as an effective HSP70-targeting anticancer drug eradicating both CSCs and non-CSCs with a minimal toxicity., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objective: This study aimed to investigate associations among spirituality, coping strategies, quality of life (QOL), and the effects of depression and anxiety thereon in cancer patients., Method: In total, 237 cancer patients referred to a psycho-oncology clinic at a university hospital in Korea were enrolled. After identifying predictors of patient QOL in a stepwise regression model, we developed a hypothetical path model wherein interpersonal coping was considered as a mediating variable between spirituality (meaning/peace) and QOL and wherein depression and anxiety affected each of these three variables., Result: The direct effect of spirituality (meaning/peace) on QOL was 36.7%. In an indirect model, interpersonal coping significantly mediated the relationship between spirituality (meaning/peace) and QOL. Depression exerted the largest negative effect on spirituality (meaning/peace), interpersonal coping, and QOL. Anxiety had negative effects on spirituality (meaning/peace) and QOL, but a positive effect on interpersonal coping., Significance of Results: Interpersonal coping strategies work as a partial mediator of the relationship between meaning/peace subscales of spirituality and QOL. Effective management of depression may help in achieving better outcomes associated therewith. Greater attention and efforts to improve social connectedness and meaning of life in spiritual well-being may improve the QOL of cancer patients.

Background: Distress in cancer patients leads to poorer quality of life (QOL) and negatively impacts survival. For efficient management of a patient's disease course, the interrelationships among distress, depression, insomnia, and QOL must be understood. This study aimed to investigate whether depression and insomnia mediate the relationship between distress and QOL in cancer patients., Methods: Cancer patients referred to a specialized psycho-oncology clinic (n=208) participated in this study. Distress, depression, insomnia, and QOL were measured with the following questionnaires: Distress Thermometer, Hospital Anxiety and Depression Scale, Insomnia Severity Index, and Functional Assessment of Cancer Therapy-General. Structural equation modeling and path analysis were performed to analyze the mediating effects of depression and insomnia on the relationship between distress and QOL., Results: Distress exerted nearly equal direct (ß=-0.291, p=0.002) and indirect (mediated by depression and insomnia) (ß=-0.299, p=0.003) negative effects on QOL. Depression exhibited the largest direct negative effect on QOL. The indirect effects of distress on QOL through depression alone, through insomnia alone, and through an insomnia to depression pathway were all significant (ß=-0.122, p=0.011; ß=-0.102, p=0.002; and ß=-0.075, p<0.001, respectively)., Limitations: The cross-sectional analyses limit the measurement of causal relationships between each variable., Conclusions: Depression and insomnia, both individually and as part of an interrelated pathway, partially mediate the relationship between distress and QOL. Appropriate interventions to alleviate insomnia and depression may mitigate the negative impacts of distress on QOL in cancer patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Recovery from DNA damage is critical for cell survival. The serious damage is not able to be repaired during checkpoint and finally induces cell death to prevent abnormal cell growth. In this study, we demonstrated that 8N-DNA contents are accumulated via re-replication during prolonged recovery period containing serious DNA damage in mitotic cells. During the incubation for recovery, a mitotic delay and initiation of an abnormal interphase without cytokinesis were detected. Whereas a failure of cytokinesis occurred in cells with no relation with p53/p21, re-replication is an anomalous phenomenon in the mitotic DNA damage response in p53/p21 negative cells. Cells with wild-type p53 are accumulated just prior to the initiation of DNA replication through a G₁ checkpoint after mitotic DNA damage, even though p53 does not interrupt pre-RC assembly. Finally, these cells undergo cell death by apoptosis. These data suggest that p53 activates G₁ checkpoint in response to mitotic DNA damage. Without p53, cells with mitotic DNA damage undergo re-replication leading to accumulation of damage.

DNA damage induces multiple checkpoint pathways to arrest cell cycle progression until damage is repaired. In our previous reports, when DNA damage occurred in prometaphase, cells were accumulated in 4 N-DNA G1 phase, and mitosis-specific kinases were inactivated in dependent on ATM/Chk1 after a short incubation for repair. We investigated whether or not mitotic DNA damage causes cells to skip-over late mitotic periods under prolonged incubation in a time-lapse study. 4 N-DNA-damaged cells re-replicated without cell division and accumulated in 8 N-DNA content, and the activities of apoptotic factors were increased. The inhibition of DNA replication reduced the 8 N-DNA cell population dramatically. Induction of replication without cell division was not observed upon depletion of Chk1 or ATM. Finally, mitotic DNA damage induces mitotic slippage and that cells enter G1 phase with 4 N-DNA content and then DNA replication is occurred to 8 N-DNA content before completion of mitosis in the ATM/Chk1-dependent manner, followed by caspase-dependent apoptosis during long-term repair., (Copyright © 2012 Elsevier Inc. All rights reserved.)