( ncer cell cultures resistant to the che...)Compound from Chinese medicine shows promise in head and neck cancer

ncer cell cultures resistant to the chemotherapy drug cisplatin, a platinum-based drug frequently used to treat this type of cancer. They found cisplatin killed cells with a mutant form of the protein p53, but cells with normal p53 and high levels of Bcl-xL were resistant. The researchers then treated these cisplatin-resistant cell lines with (-)-gossypol and found that (-)-gossypol induced the drug resistant tumor cells to undergo programmed cell death.

"These cisplatin resistant cells are exquisitely sensitive to (-)-gossypol. We can induce cell death in 70 percent to 90 percent of cells. This is a very impressive induction of cell death. It's because we are targeting the pathways these cells need to survive," says study author Thomas Carey, Ph.D., co-director of the Head and Neck Oncology Program at the U-M Comprehensive Cancer Center and a professor in the U-M School of Dentistry and the U-M Medical School.

To test the principle that Bcl-xL and non-mutant p53 determine resistance to cisplatin in head and neck cancer cells, lead study author Joshua Bauer, a U-M graduate student in pharmacology, overexpressed Bcl-xL in tumor cells with mutant or non-mutant p53. Only cells with non-mutant p53 and high Bcl-xL became resistant to cisplatin. Bauer then treated these cells with (-)-gossypol and induced cell death.

To further confirm the importance of Bcl-xL in cisplatin resistance, the researchers used a technique called inhibitory RNA to shut off expression of Bcl-xL in the drug-resistant cells. These cells became sensitive to cisplatin when Bcl-xL was turned off, confirming its role in drug resistance.

"We believe novel agents that target Bcl-xL can improve survival for our patients," Carey says.

In a previous study published in November 2004 in Clinical Cancer Research, Bradford, Carey and their team treated cell cultures of head and neck squamous cell carcinoma with the (-)-gossypol compound and found it inhibited tumor cell
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Source:University of Michigan Health System

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