Marijuana ingredient inhibits VEGF pathway required for brain tumor blood vessels

Cannabinoids, the active ingredients in marijuana, restrict the sprouting of blood vessels to brain tumors by inhibiting the expression of genes needed for the production of vascular endothelial growth factor (VEGF).

According to a new study published in the August 15, 2004 issue of the journal Cancer Research, administration of cannabinoids significantly lowered VEGF activity in laboratory mice and two patients with late-stage glioblastoma.

“Blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available,” said Manuel Guzmán, professor of biochemistry and molecular biology, with the Complutense University in Madrid, Spain, and the study’s principal investigator. “The present findings provide a novel pharmacological target for cannabinoid-based therapies.”

Glioblastoma multiforme, the most aggressive form of glioma, strikes more than 7,000 Americans each year and is considered one of the most malignant and deadliest forms of cancer, generally resulting in death within one to two years following diagnosis.

The disease is usually treated with surgery, followed by conventional radiation alone or in combination with chemotherapy. However, the main tumor often evades total destruction, surviving and growing again, eventually killing the patient. For this reason, researchers are actively seeking other therapeutic strategies, some of which might be considered novel.

In this study, the investigators chose to work with cannabinoids which, in previous studies, have been shown to inhibit the growth of blood vessels, or angiogenesis, in laboratory mice. However, little was known about the specific mechanisms by which cannabinoids impair angiogenesis, or whether the chemical might do the same in human tumors.

To answer the first part of the question, the scientists induced gliomas in mice, which were subsequently inoculated with cannabinoids. Using DNA array analysis, the team examined 267 genes associated with the growth of blood vessels in tumors and found that cannabinoids lowered the expression of several genes related to the VEGF pathway, critical for angiogenesis.

The researchers also discovered that cannabinoids apparently worked by increasing the activity of ceramide, a lipid mediator of apoptosis, resulting in the functional inhibition of cells needed for VEGF production. The ability of cannabinoids to alter VEGF production was significantly stifled following the introduction of a ceramide inhibitor.

“As far as we know, this is the first report showing that ceramide depresses VEGF pathway by interfering with VEGF production,” according to Guzmán.

To answer the second part of the question relating to clinical tests, the scientists obtained tumor biopsies from two patients with glioblastomas who had failed standard therapy, including surgery, radiotherapy and chemotherapy. The biopsied tissue was analyzed before and after local injection of a cannabinoid.

“In both patients, VEGF levels in tumor extracts were lower after cannabinoid inoculation,” said Guzmán. The results, he added, suggest a potential new approach toward the treatment of these otherwise intractable brain tumors. “It is essential to develop new therapeutic strategies for the management of glioblastoma multiforme,” the scientists wrote, “which will most likely require a combination of therapies to obtain significant clinical results.”

Also participating in the study were Cristina Blázquez and Amador Haro, from Complutense University; Luis González-Feria, from University Hospital, Tenerife, Spain; Luis Álvarez, from La Paz University Hospital in Madrid; and M. Llanos Casanova, from the Project on Cellular and Molecular Biology and Gene Therapy, CIEMAT, also in Madrid.