Agent orange chemical, dioxin, attacks the mitochondria to cause cancer, says Penn research team

Contact: Jordan Reese
jreese@upenn.edu
215-573-6604
University of Pennsylvania

PHILADELPHIA— Researchers with the University of Pennsylvania School of Veterinary Medicine have demonstrated the process by which the cancer-causing chemical dioxin attacks the cellular machinery, disrupts normal cellular function and ultimately promotes tumor progression.

The team identified for the first time that mitochondria, the cellular sub-units that convert oxygen and nutrients into cellular fuel, are the target of tetrachlorodibenzodioxin, or TCDD. The study showed that TCDD induces mitochondria-to-nucleus stress signaling, which in turn induces the expression of cell nucleus genes associated with tumor promotion and metastasis.

The mechanism the research team has described is directly relevant to understanding incidences of breast and other cancers in human populations exposed to these chemicals. With a better understanding of this underlying cellular mechanism, researchers hope to improve their understanding of tumor growth and promotion.

“Now that we have identified this signaling mechanism we can look at ways to disrupt this complex chain of events,” said Narayah Avadhani, chair of the Department of Animal Biology at Penn’s School of Veterinary Medicine and the study’s lead investigator. “Our ultimate goal is to block the propagation of this mitochondrial stress signaling and inhibit the expression of the proteins that combine to assist cancer growth.”

A well-characterized mechanism of TCDD action occurs through activation of arylhydrocarbon receptors, AhR, by directly binding to the protein subunits. Activated AhR mediates the transcriptional activation of many genes including those involved in fatty acid metabolism, cell cycle regulation and immune response. The present study, however, shows that TCDD starts the chain of events that promote tumor progression in vivo by directly targeting mitochondrial transcription and induction of mitochondrial stress signaling. A unique feature of this TCDD-induced signaling is that it does not involve the action of AhR but occurs through increased calcium levels in cells and activation of calcium responsive factors. A net result of signaling cascade is slowing down of cellular apoptosis, increased cell proliferation and tumor cell metastasis. Taken together, this study describes a novel mechanism of TCDD-induced tumor progression and emergence of metastatic cancer cells.

TCDD is the most toxic compound in the dioxin family. Formed as a by-product during waste incineration, paper, chemical and pesticide manufacturing, it was the toxic ingredient in Agent Orange and closed the Love Canal in Niagara Falls. The public health impact of dioxin, according to the Environmental Protection Agency, compares to that of the pesticide DDT.

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The study appears online and in the Dec. 17 issue of the Proceedings of the National Academy of Sciences and was performed by Avadhani, Gopa Biswas, Satish Srinivasan and Hindupur Anandatheerthavarada of the Penn School of Veterinary Medicine.

The research was supported by a grant from the National Cancer Institute and the National Institutes of Health.

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Cognitive therapy can reduce post-traumatic stress in survivors of terrorist attacks

Contact: Emma Dickinson
edickinson@bmj.com
44-020-738-36529
BMJ-British Medical Journal

Post-traumatic stress disorder in the context of terrorism and other civil conflict in Northern Ireland: randomised controlled trial
Cognitive therapy is an effective treatment for post-traumatic stress disorder related to acts of terrorism and other civil conflict, finds a study published on bmj.com today.

Recent NICE guidelines recommend cognitive behaviour therapy as a treatment of choice (alone or in conjunction with drugs) for post-traumatic stress disorder. However, this recommendation is largely based on trials focusing on non-terrorism related traumatic events, such as road traffic crashes and rape. Little is known about how to best treat those traumatised by terrorist incidents.

So researchers at the Northern Ireland Centre for Trauma and Transformation undertook the first controlled trial aimed at assessing the effectiveness of cognitive therapy for people affected by terrorism and other civil conflict.

The trial involved 58 people with chronic post-traumatic stress disorder, mostly resulting from multiple traumas linked to terrorism and other civil conflict.

Patients were split into two groups, the first received immediate cognitive therapy while the other group were placed on a 12 week waiting list, followed by treatment.

Levels of post-traumatic stress disorder and depression were measured at the start of the trial and at the end of the treatment period. Work and social functioning was also assessed in both groups. Further assessments were carried out after one, four and 12 months.

At 12 weeks, patients in the immediate therapy group showed significant and substantial reductions in the symptoms of post-traumatic stress disorder and depression. In contrast, patients in the waiting list group showed no change.

The therapy group also had improved levels of work and social functioning. Thirty-eight per cent of those in the waiting list group deteriorated during the 12 week period compared to just seven per cent the therapy group. The treatment gains made were well maintained at the follow-up assessments.

The improvements made by those in the therapy group varied between individuals. The authors suggest this may be in part due to the complexity of the problems and in part due to the methods of the therapist. It is recommended that therapists involved in this sort of therapy are given sufficient training and ongoing supervision.

They conclude that cognitive therapy is effective in the treatment of post-traumatic stress disorder related to terrorism and other civil conflict.

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