Mar.
14, 2013 — Researchers have identified an elusive anti-cancer property of
vitamin E that has long been presumed to exist, but difficult to find.
Many
animal studies have suggested that vitamin E could prevent cancer, but human
clinical trials following up on those findings have not shown the same
benefits.
In
this new work, researchers showed in prostate cancer cells that one form of
vitamin E inhibits the activation of an enzyme that is essential for cancer
cell survival. The loss of the enzyme, called Akt, led to tumor cell death. The
vitamin had no negative effect on normal cells.
"This
is the first demonstration of a unique mechanism of how vitamin E can have some
benefit in terms of cancer prevention and treatment," said lead author
Ching-Shih Chen, professor of medicinal chemistry and pharmacognosy at The Ohio
State University and an investigator in Ohio State's Comprehensive Cancer Center.
The
study appears in the March 19, 2013, issue of the journal Science
Signaling.
Chen
cautioned that taking a typical vitamin E supplement won't offer this benefit
for at least two reasons: The most affordable supplements are synthetic and
based predominantly on a form of the vitamin that did not fight cancer as
effectively in this study, and the human body can't absorb the high doses that
appear to be required to achieve the anti-cancer effect.
"Our
goal is to develop a safe pill at the right dose that people could take every
day for cancer prevention. It takes time to optimize the formulation and the
dose," he said.
Chen
has filed an invention disclosure with the university, and Ohio State has filed
a patent application for the agent.
Vitamin
E occurs in numerous forms based on their chemical structure, and the most
commonly known form belongs to a variety called tocopherols. In this study,
researchers showed that, of the tocopherols tested, the gamma form of
tocopherol was the most potent anti-cancer form of the vitamin.
The
scientists manipulated the structure of that vitamin E molecule and found that
the effectiveness of this new agent they created was 20-fold higher than the
vitamin itself in cells. In experiments in mice, this agent reduced the size of
prostate cancer tumors.
These
findings suggest that an agent based on the chemical structure of one form of
vitamin E could help prevent and treat numerous types of cancer -- particularly
those associated with a mutation in the PTEN gene, a fairly common cancer-related
genetic defect that keeps Akt active.
The
researchers began the work with both alpha and gamma forms of the vitamin E
molecule. Both inhibited the enzyme called Akt in very targeted ways, but the
gamma structure emerged as the more powerful form of the vitamin.
In
effect, the vitamin halted Akt activation by attracting Akt and another
protein, called PHLPP1, to the same region of a cell where the vitamin was
absorbed: the fat-rich cell membrane. PHLPP1, a tumor suppressor, then launched
a chemical reaction that inactivated Akt, rendering it unable to keep cancer
cells alive.
"This
is a new finding. We have been taking vitamin E for years but nobody really
knew about this particular anti-cancer mechanism," Chen said.
The
gamma form was most effective because its chemical shape allowed it to attach
to Akt in the most precise way to shut off the enzyme.
Because
of how the various molecules interacted on the cell membrane, the scientists
predicted that shortening a string of chemical groups dangling from the main
body, or head group, of the gamma-tocopherol molecule would make those
relationships even stronger. They lopped off about 60 percent of this side
chain and tested the effects of the new agent in the prostate cancer cells.
"By
reducing two-thirds of the chain, the molecule had a 20 times more potent
anti-tumor effect, while retaining the integrity of vitamin E's head
group," Chen said. This manipulation enhanced the anti-tumor potency of
the molecule by changing its interaction with the cell membrane, so that the
head group was more accessible to Akt and PHLPP1.
When
mice with tumors created by these two prostate cancer cell lines were injected
with the agent, the treatment suppressed tumor growth when compared to a
placebo, which had no effect on tumor size. Chemical analysis of the treated
tumors showed that the Akt enzyme signal was suppressed, confirming the effects
were the same in animals as they had been in cell cultures.
The
animal study also suggested the experimental agent was not toxic. Chen's lab is
continuing to work on improvements to the molecule.
This
work was supported by the National Institutes of Health.
Co-authors
include Po-Hsien Huang, Hsiao-Ching Chuang, Chih-Chien Chou, Huiling Wang,
Su-Lin Lee, Hsiao-Ching Yang, Hao-Chieh Chiu, Naval Kapuriya, Dasheng Wang and
Samuel Kulp of the Division of Medicinal Chemistry and Pharmacognosy at Ohio
State. Huang and Chen also are affiliated with National Cheng-Kung University,
Yang with Fu-Jen Catholic University, and Chiu with National Taiwan University,
all in Taiwan; and Kapuriya with Saurashtra University in Gujarat, India.
Source:
http://www.sciencedaily.com/releases/2013/03/130314175659.htm
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