Can a lowly spice help fight the battle against pediatric brain tumors?
Maybe, according to preliminary research published in a recent issue of BMC Cancer. Curcumin, a major component of the spice turmeric, has been shown to have chemopreventive and chemotherapeutic properties. Past research also demonstrates that it has the potential to destroy human medulloblastoma cells cultured in the laboratory.
In the current study, researchers were able to identify a protein as a candidate biomarker in order to better predict which patients might respond favorably to curcumin therapy.
This work is exciting because right now, the prognosis of childhood brain tumors is generally poor, treatment options are limited, and children often have long-term side effects from treatment, explained lead author Sigrid Langhans, PhD, senior research scientist at the Nemours Center for Childhood Cancer Research at the Alfred I. duPont Hospital for Children, Wilmington, Delaware. The team is now planning clinical trials with curcumin.
"The problem is that many drugs which could be effective do not make it across the blood-brain barrier," she pointed out. "The blood-brain barrier protects the brain from toxic substances but unfortunately also prevents therapeutic agents from entering as well."
But one of the interesting things about curcumin is that it can cross the blood-brain barrier, she told Medscape Medical News in an interview.
Curcumin can induce apoptosis in a variety of tumor cells and has also prevented tumor initiation and growth in experimental models. Dr. Langhans and her team, along with other groups, have previously shown that curcumin induces cell death in medulloblastoma, the most common pediatric brain tumor, and inhibited tumor growth in in vivo medulloblastoma models.
But it is not clear why curcumin selectively targets tumor cells, although it has been suggested that it affects signaling pathways that regulate cell growth and survival and thus preferably will induce apoptosis in highly proliferating cells. "So in this study we followed up on studying the mechanisms which might explain how it can induce cell death," Dr. Landhans explained.
Drawing on their earlier research, the authors found that curcumin specifically binds to and crosslinks to a protein that is involved in cell-cycle regulation. It is known as a checkpoint protein, she said, because it blocks the onset of anaphase until all chromosomes make proper attachments to the spindle. The mitotic checkpoint, or spindle assembly checkpoint (SAC), is the major cell-cycle control mechanism that delays the onset of anaphase during mitosis. One of the primary regulators of the SAC is the anaphase-promoting complex/cyclosome (APC/C).
"But if there is a defect in the checkpoint, this process is disrupted," Dr. Langhans added. "So this study may show why curcumin causes death in tumor cells but not in normal cells. That is the great thing about curcumin because if it only targets tumor cells, then it has very few — if any — side effects."
Because the APC/C not only ensures that the cell cycle will be halted during spindle disruption but also promotes cell death in response to prolonged mitotic arrest, the authors note, it has become an attractive drug target for cancer therapy.
Preference for Phosphorylated Cells
The authors also found that tumors treated with curcumin had lower levels of Cdc27, and subsequently identified Cdc27/APC3, which is a component of the APC/C, as a novel molecular target of curcumin. They found that curcumin binds to and crosslinks Cdc27 to affect APC/C function.
In addition, they found that curcumin binds more resolutely to this specific protein when it is phosphorylated, a modification that is generally seen in rapidly proliferating cells, such as in tumors.
"It much more strongly induces death in these cells, so we can probably use that as a biomarker to predict which patients might respond to curcumin therapy," Dr. Langhans said. "And this isn't just for children but for all patients. We might be able to predict who may respond more favorably to this treatment, and then treatment can be adjusted accordingly."
Knowing the mechanism behind curcumin's antitumor mechanism will help in developing therapeutic agents. "We can then rationally design drugs that may be more effective — that is our long term goal," she explained.
Dr. Langhans noted that the next step is to move their research into the clinic. "We hope to begin clinical trials," she said. "Our first priority will be pediatric brain tumors. We will first see how curcumin responds in pediatric patients and then we will next try to specifically target the patients that might derive the most benefit."
The study was funded by the Nemours Foundation. The authors have disclosed no relevant financial relationships.
BMC Cancer. 2012;12:44. Full text