The findings, which appear in the July issue of the journal Molecular Cancer Therapeutics, could lead to a treatment that provides an effective option to surgically removing the cancer, helping patients preserve vital organs involved in speech and swallowing.
While new treatments in head and neck cancer have allowed some patients to undergo chemotherapy and radiation therapy instead of surgery, this form of cancer is often resistant to chemotherapy. When the cancer does not respond to these powerful drugs, patients must resort to surgery.
"Patients really benefit long-term by avoiding surgery because the side effects of surgery for head and neck cancer can be particularly difficult for patients. It affects how you talk, how you swallow and how you breathe," says study author Carol Bradford, M.D., professor of otolaryngology at the U-M Medical School and co-director of the Head and Neck Oncology Program at the U-M Comprehensive Cancer Center.
The compound, (-)-gossypol, works to regulate a protein called Bcl-xL that's overexpressed in cancer cells and makes these cells survive when they shouldn't. Shaomeng Wang, Ph.D., co-director of the Molecular Therapeutics Program at the U-M Comprehensive Cancer Center, discovered (-)-gossypol, a compound derived from a component of Chinese medicine.
Gossypol comes from cottonseed and was once used in China as a male contraceptive. More recently, it's been tested as a cancer treatment. Wang found the negative isomer of gossypol binds at a site to block the active Bcl-xL protein. A prior study conducted by researchers in the U-M Head and Neck Oncology Program showed Bcl-xL protein is often highly expressed in head and neck cancers.
In this study, researchers developed head and neck ca 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 growth. Additional testing in animals was also positive and showed (-)-gossypol did not harm surrounding healthy tissue.
Researchers hope to begin a clinical trial in head and neck cancer patients within a year, testing whether (-)-gossypol can be used along with chemotherapy to create a better response and avoid surgery.
More than 29,000 people will be diagnosed in 2005 with head and neck cancers, which include cancer of the tongue, mouth, throat and voice box.
University of Michigan holds a patent on the negative isomer, (-)-gossypol, and has licensed the technology to Ascenta Therapeutics of San Diego, Calif., for commercial development. Wang is one of three U-M Medical School faculty members who founded the company and has significant financial interest.