Compound
from Chinese medicine shows promise in head and neck
cancer
Medical News Today.com
19 july 2005
A compound derived from cottonseed could
help improve the effectiveness of chemotherapy at
treating head and neck cancer, researchers at the
University of Michigan Comprehensive Cancer Center
have found.
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
cancer 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.
The study was funded by the U-M head and neck cancer
Specialized Program of Research Excellence (SPORE)
grant, the National Cancer Institute and the
National Institute of Dental and Craniofacial
Research. Additional authors were U-M research
assistants Bhavna Kumar Jason Castro, Julia
Shin-Jung Lee and Jianyong Chen; former U-M resident
Douglas Trask, now assistant professor at the
University of Iowa; and Gerrit Los from Pfizer
Global Research and Development.
To learn more about head and neck cancer, call the
Cancer AnswerLine at (800) 865-1125 or visit
www.cancer.med.umich.edu/clinic/headneckclinic.htm.
Reference: Molecular Cancer Therapeutics, Vol. 4,
No. 7, pp. 1096-1104.
Nicole Fawcett
nfawcett@umich.edu
734-764-2220
Kara Gavin
kegavin@umich.edu
734-764-2220
University of Michigan Health System
http://www.umich.edu
