Mechanism found for DIM in reducing ovarian cancer cell growth
Tuesday, January 31, 2012. In the journal BMC Medicine on January 26, 2012, Professor Sanjay K. Srivastava and Prabodh K. Kandala of Texas Tech University Health Sciences Center in Amarillo report the discovery of a mechanism for diindolylmethane (DIM), an active metabolite of indole-3-carbinol found in cruciferous vegetables, to induce programmed cell death (apoptosis) in cultured ovarian cancer cells.
Previous research uncovered an inhibitory effect for DIM on ovarian cancer cell growth, yet the mechanism involved remained unknown. The current study explored the effects of DIM in several ovarian cancer lines. Drs Srivastava and Kandala found that DIM induces apoptosis, and that it exerts its effects by blocking the production and activation of signal transducer and activator of transcription 3 (STAT3), a transcription factor that is associated with the growth and survival of cells which is over-expressed in cases of resistance to the chemotherapy cisplatin. DIM also reduced the proinflammatory cytokine interleukin-6 in ovarian tumor cells, and inhibited cell invasion and angiogenesis via suppression of hypoxia-inducible factor 1-alpha and vascular epithelial growth factor.
In further experimentation, the duo pretreated ovarian cancer cells with DIM, followed by the administration of cisplatin for 24 hours. The combination of DIM and cisplatin resulted in a 50 to 70 percent reduction in cell survival, in contrast with a 28 percent reduction in cells treated with cisplatin alone. Furthermore, mice treated with DIM alone or DIM and cisplatin experienced retarded growth of implanted ovarian tumors compared to untreated mice or animals that received cisplatin alone. "Our results demonstrate that DIM suppresses the growth of ovarian cancer cells and potentiates the effect of cisplatin in vitro and in vivo by targeting STAT3 signaling without being toxic to normal ovarian cells," the authors write. "To the best of our knowledge, this is the first report demonstrating STAT3 as a target of DIM."
"Cisplatin is very toxic and has severe side effects," Drs Srivastava and Kandala explained. "If co-treatment with DIM means that a low dose of cisplatin can be given to patients without the loss of therapeutic effect, but with reduced side effects, it would represent a significant breakthrough in clinical practice."
An article published online on October 17, 2011 in the Journal of Clinical Investigation revealed that sulforaphane, a compound that occurs in broccoli and other cruciferous vegetables, improves sensitivity to corticosteroid drugs used to treat chronic obstructive pulmonary disease (COPD), a condition that is mainly the result of smoking, characterized by chronic bronchitis and emphysema. The disease is currently treated with corticosteroids, however, the drugs only reduce symptoms by approximately 20 percent.
Individuals diagnosed with COPD experience a reduction in their lungs of histone deacetylase 2 (HDAC2), a substance that is essential to the anti-inflammatory pathway initiated by steroid drugs. In the current research, a team from Johns Hopkins University discovered that S-nitrosylation of HCAC2 due to cigarette smoke exposure resulted in HDAC2 dysfunction in lung macrophages derived from individuals with COPD. "This study provides the mechanism of exaggerated inflammation observed in COPD patients during exacerbations, which has been a barrier to developing effective therapy," stated coauthor Rajesh Thimmulappa, PhD, who is an assistant scientist at Johns Hopkins Bloomberg School of Public Health's Department of Environmental Health Sciences.
It was further discovered that sulforaphane denitrosylates HDAC2, which restored corticosteroid sensitivity. In previous research, the team demonstrated that sulforaphane activates a pathway known as Nrf2. "Restoring corticosteroid sensitivity in patients with COPD by targeting the Nrf2 pathway holds promise for effectively treating exacerbations," noted senior author Shyam Biswal, PhD, who is a professor at the Bloomberg School's Department of Environmental Health Sciences and Division of Pulmonary and Critical Care Medicine.
"Nrf2 activators such as sulforaphane can counteract oxidative and nitrosative stress and mediate glutathione-dependent denitrosylation, thereby restoring HDAC2 activity," the authors write. "The small-molecule Nrf2 activator sulforaphane may be useful as an adjuvant therapy to augment the antiinflammatory effects of glucocorticosteroids in COPD and other inflammatory diseases."
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Hunger is the factor that often precludes most people from even considering a low-calorie diet. Pinolenic acid, from the Korean Pine Nut, stimulates the release of two of the body's most powerful hunger-suppressing hormones: CCK (cholecystokinin) and GLP-1 (glucagon-like peptide-1). This sends a feeling of satiety or fullness to the brain, decreasing the desire to eat and helping to control excessive calorie intake. People taking this oil had an increase in the satiety hormones CCK and GLP-1 in the bloodstream and a 36% reduced desire to eat.
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