Protein kinase C-D (PKCD) plays an important role in DNA damage-induced apoptosis. We have previously shown that the PKCD inhibitor rottlerin protects against cisplatin-induced apoptosis acting upstream of caspase-9. In the present study, we have investigated if rottlerin regulates caspase-2 activation. Knockdown of caspase-2 by siRNA inhibited processing of apical caspase-9 and caspase-8, whereas depletion of caspase-9 had little effect on caspase-2 processing. Rottlerin inhibited activation and processing of caspase-9 and caspase-8 and cleavage of poly(ADP)ribose polymerase. We made a novel observation that rottlerin induced down-regulation of caspase-2 but not of caspase-3, caspase-7, caspase-8, or caspase-9. Pharmacologic inhibitors of PKC, such as Gö 6983 and bisindolylmaleimide, or depletion of PKCD by siRNA had no effect on the down-regulation of caspase-2 by rottlerin. The proteasome inhibitor MG132 reversed caspase-2 down-regulation by rottlerin, whereas calpain inhibitor had no effect. These results suggest that rottlerin induces down-regulation of caspase-2 via PKCD-independent but ubiquitin proteasome-mediated pathway. Furthermore, down-regulation of caspase-2 by rottlerin can explain its antiapoptotic function during DNA damageinduced apoptosis. [Cancer Res 2008;68(8):2795-802]

BackgroundMore than two-fifths of the world’s population uses solid fuels, mostly biomass, for cooking. The resulting biomass smoke exposure is a major cause of chronic obstructive pulmonary disease (COPD) among women in developing countries.ObjectiveTo assess whether lower woodsmoke exposure from use of a stove with a chimney, compared to open fires, is associated with lower markers of airway inflammation in young women.DesignWe carried out a cross-sectional analysis on a sub-cohort of participants enrolled in a randomized controlled trial in rural Guatemala, RESPIRE.ParticipantsWe recruited 45 indigenous women at the end of the 18-month trial; 19 women who had been using the chimney stove for 18–24 months and 26 women still using open fires.MeasurementsWe obtained spirometry and induced sputum for cell counts, gene expression of IL-8, TNF-α, MMP-9 and 12, and protein concentrations of IL-8, myeloperoxidase and fibronectin. Exhaled carbon monoxide (CO) and 48-hr personal CO tubes were measured to assess smoke exposure.ResultsMMP-9 gene expression was significantly lower in women using chimney stoves. Higher exhaled CO concentrations were significantly associated with higher gene expression of IL-8, TNF-α, and MMP-9. Higher 48-hr personal CO concentrations were associated with higher gene expression of IL-8, TNF- α, MMP-9 and MMP-12; reaching statistical significance for MMP-9 and MMP-12.ConclusionsCompared to using an open wood fire for cooking, use of a chimney stove was associated with lower gene expression of MMP-9, a potential mediator of airway remodeling. Among all participants, indoor biomass smoke exposure was associated with higher gene expression of multiple mediators of airway inflammation and remodeling; these mechanisms may explain some of the observed association between prolonged biomass smoke exposure and COPD.

Plasma Catecholamine Levels and Neurobehavioral Problems in Indian Firefighters: Manas R. RAY, et al. Experimental Hematology Unit, Chittaranjan National Cancer Institute, IndiaFirefighting is a stressful and hazardous job. Persons engaged in firefighting are highly exposed to workrelated stress as well as to smoke containing a host of chemicals potentially harmful to human health. In order to elucidate whether firefighting affects neuroendocrine and behavioral responses of firefighters, plasma catecholamine (CA) levels and the prevalence of neurobehavioral symptoms in 62 firefighters (all males, mean age 43 yr) and 52 control subjects matched for age and sex were examined in this study. Self-reported neurobehavioral symptoms data were obtained from a questionnaire survey and personal interview. Concentrations of epinephrine (E), norepinephrine (NE) and dopamine (DA) in plasma were measured by highp e r f o r m a n c e l i q u i d c h r o m a t o g r a p h y w i t h electrochemical detection. Compared with matched controls, the firefighters showed higher prevalence (p<0.05) of neurobehavioral symptoms such as burning sensation in the extremities, tingling and numbness, transient loss of memory, and depression, but no significant difference was recorded in the prevalences of anxiety, vertigo and dizziness. The firefighters demonstrated a more than two-fold (p<0.05) rise in plasma levels of E and NE, but the plasma DA level was relatively unchanged. Controlling age and smoking as possible confounders, firefighting was found to be associated with raised E (OR=2.15; 95% CI, 0.98-4.52), and NE levels (OR=2.24 95% CI, 1.22-3.61).In conclusion, the job of firefighting appears to be associated with stimulation of sympathetic activity and a rise in the prevalence of neurobehavioral symptoms. (J Occup Health 2006; 48: 210-215)

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BackgroundOvarian cancer is the leading cause of death among gynecological cancers. Cisplatin is one of the most effective anticancer drugs used in the treatment of ovarian cancer. Development of resistance to cisplatin limits its therapeutic use. Most of the anticancer drugs, including cisplatin, are believed to kill cancer cells by inducing apoptosis and a defect in apoptotic signaling can contribute to drug resistance. The tumor suppressor protein p53 plays a critical role in DNA damage-induced apoptosis. During a yeast-based drug screening, NSC109268 was identified to enhance cellular sensitivity to cisplatin. The objective of the present study is to determine if p53 is responsible for cisplatin sensitization by NSC109268.ResultsNSC109268 enhanced sensitivity of ovarian cancer 2008 cells and its cisplatin resistant counterpart 2008/C13* cells which express wild-type p53. The potentiation of cisplatin sensitivity by NSC109268 was greater in 2008/C13* cells compared to 2008 cells. Cisplatin caused a concentration-dependent increase in p53 in 2008 and 2008/C13* cells, and the induction of p53 correlated with cisplatin-induced apoptosis as determined by the cleavage of PARP. NSC109268 alone had no effect on p53 but it enhanced p53 level in response to cisplatin. Knockdown of p53 by siRNA, however, did not attenuate cell death in response to cisplatin or combination of NSC109268 and cisplatin.ConclusionsThese results demonstrate that NSC109268 enhances sensitivity of ovarian cancer 2008 cells to cisplatin independent of p53.