HERSHEY, PA-A Penn State College of Medicine study shows for the first time
in an animal model that ceramide, a naturally occurring substance that prevents
the growth of cells, can be administered through the blood stream to target
and kill cancer cells.
"Ceramide is the substance that accumulates in cancer
tissues and helps to kill cancer cells when patients
undergo chemotherapy and radiation," said Mark Kester,
Ph.D., professor of pharmacology, Penn State College
of Medicine, Penn State Milton S. Hershey Medical
Center. "By boosting the amount of ceramide through
an injection in the bloodstream, our study in mice
suggests that we can provide a stronger cancer-killing
therapy without additional side effects."
This study titled "Systemic Delivery of Liposomal
Short-Chain Ceramide Limits Solid Tumor Growth in
Murine Models of Breast Adenocarcinoma" was published
in the May issue of Clinical Cancer Research, a journal
of the American Association for Cancer Research.
Administering extra ceramide is not as easy as it
seems. Injected directly into the bloodstream, ceramide
is toxic. But Kester applied knowledge gained from
previous laboratory studies in nanotechnology and
encapsulated the ceramide in tiny bundles called
"The major problem with ceramide is that it is a
lipid and therefore is not soluble in the systemic
circulation," Kester said. "Packaging ceramide in
our nano liposome capsules allows them to travel
through the bloodstream without causing toxicity
and release the ceramide in the tumor."
Although the mechanism remains unknown, ceramide
is inherently attracted to tumor cells. The liposome-encased
ceramide travels through the bloodstream to the tumor
where it enters the tumor cells through the tumor's
leaky vasculature. The ceramide disrupts the mitochondria,
which act as the energy producer for the cell. This
causes apoptosis, or cell death. The ceramide also
reduces the vascular network that feeds the tumor.
In this study in mice, the ceramide bundles targeted
and destroyed only breast cancer cells, sparing the
surrounding healthy tissue.
Kester and his team first tested the ceramide-filled
liposomes in a culture of breast cancer cells. The
administration of ceramide reduced by more than 50
percent the number of breast cancer cells. Additional
cell culture studies showed that ceramide accumulated
in the mitochondria of the breast cancer cells supporting
earlier laboratory studies that ceramide interferes
with the structure of the cell and causes tumor death.
In a mouse model of breast tumors, the team administered
liposome-encased ceramide every other day via intravenous
injection. After 21 days, the mice treated with the
liposome-encased ceramide had a six-fold lower tumor
volume than the mice treated with "empty" liposomes.
The weight of animals treated with ceramide did not
vary significantly from the mice treated with empty
liposomes signifying that the ceramide was not toxic
(weight would have been lower with toxicity). When
the tumors were examined, those treated with ceramide
showed a 20-fold increase in cellular apoptosis and
a 40 percent decrease in cellular proliferation,
or growth, compared to the control group.
"Although we've shown that ceramide has an effect
on breast tumor cells in mice, breast cancer cells
in humans may eventually resist the treatment, suggesting
that ceramide should be used in combination with
more traditional cancer treatments as a treatment
booster," Kester said. "Our next step is to explore
how additional chemotherapeutic agents could be incorporated
into the liposomes for a more lasting effect."
Other study team members were: Thomas C. Stover,
Ph.D., Arati Sharma, Ph.D., Department of Pharmacology,
and Gavin P. Robertson, Ph.D., Departments of Pharmacology,
Pathology, and Dermatology, Penn State College of
Medicine, Penn State Milton S. Hershey Medical Center.
All research methods were approved by the Animal
Care and Use Committee of Penn State College of Medicine.
This study was supported by a grant from the National
Institutes of Health.
Contact: Valerie Gliem