Xiaoqi Liu (pronounced zhow-CHEE' LEE'-oo), associate professor of biochemistry and cancer research,
and fellow researchers found that the drugs metformin and BI2536 can
work together to suppress the spread of prostate cancer that resists all
other available treatments, potentially prolonging patients' lives.
"We've found a promising way to treat late-stage
prostate cancer," Liu said. "By combining low levels of two
well-tolerated drugs, the progression of this disease could be
significantly delayed. Completely curing the cancer at the advanced
stage is pretty much impossible, but this treatment might manage it for a
while - that's exciting."
A number of treatments exist for the earlier
stages of prostate cancer, which grows slowly compared with many other
cancers. Because prostate cancer cells need the male sex hormone
androgen to develop, one way to treat the disease is to suppress
androgen - a process known as castration. If the cancer continues to
spread, the patient often undergoes chemotherapy. As a last resort,
drugs that block the synthesis of androgen by prostate cancer cells can
be used, but these medications only extend a patient's lifespan for
several months.
New approaches to treating the most persistent forms of prostate cancer are "urgently needed," Liu said.
Adding to the challenge is the fact that
castration treatment can inadvertently encourage the cancer to get
tougher. It can heighten oxidative stress on the prostate gland, which
increases the expression of Plk1, a gene that has been linked to many
cancers. Over-expression of Plk1 can also trigger the synthesis of
androgen.
"The goal of castration is to block androgen
synthesis," Liu said. "But cancer cells eventually become 'smart' enough
to make androgen anyhow, which is why the cancer continues to grow."
Additionally, castration can disrupt the body's
metabolism and lead to insulin resistance, which also can stimulate the
production of androgen. The cancer will spread until both of these side
effects are stopped, Liu said.
Previous studies showed that metformin - an
inexpensive, antidiabetic drug that has been commonly used for more than
40 years - is particularly potent to prostate cancer tumors.
Working with fellow researchers from Purdue, the
University of Wisconsin-Madison and the Indiana University School of
Medicine, Liu found that a combination of low levels of metformin and
BI2536, a drug that stifles the activity of Plk1, could work in tandem
to slow the growth of prostate tumors too advanced for current
treatments by promoting the self-destruction of cancer cells and
preventing androgen synthesis.
The drugs did not impact healthy prostate cells, a
"key finding," Liu said. "Ideally, cancer therapy will have minimal
effects on normal cells."
Because metformin helps regulate metabolism, it may reverse some of the metabolic damage caused by castration, he said.
The researchers tested the drugs in a classical
cell culture assay of prostate cancer cells and in advanced prostate
tumors in mice. Low concentrations of the drugs significantly slowed the
development of cancer in both trials. The mice tumors were grown from
the tumor cells of a late-stage prostate cancer patient, suggesting that
the treatment would prove effective in humans.
"Those results were amazing," Liu said. "These
are the first data we've generated from a real patient, so I was almost
jumping in the air when I saw that it worked."
Liu said that the next step in the research is to
test the combination of drugs in clinical trials. Further research is
also needed to understand the underlying mechanism of metformin and why
it is effective at suppressing prostate cancer.
The paper was published in the Journal of Biological Chemistry on Jan. 24 and is available at http://www.jbc.org/content/290/4/2024.full.
The National Institutes of Health, the National
Science Foundation, the American Cancer Society and the China
Scholarship Council provided funding for the research.
Writer: Natalie van Hoose, 765-496-2050, nvanhoos@purdue.edu
Source: Xiaoqi Liu, 765-496-3764, liu8@purdue.edu
Related news release:
Genes may be good target for tough-to-kill prostate cancer cells: http://www.purdue.edu/newsroom/research/2011/110926LiuPten.html