An experimental drug, BHPI, binds to the estrogen receptor and disrupts the growth of cancer cells. Credit: Neal Andruska
An experimental drug rapidly shrinks most tumors in a mouse model of human breast cancer, researchers report in the Proceedings of the National Academy of Sciences. When mice were treated with the experimental drug, BHPI, "the tumors immediately stopped growing and began shrinking rapidly," said University of Illinois biochemistry professor and senior author David Shapiro. "In just 10 days, 48 out of the 52 tumors stopped growing, and most shrank 30 to 50 percent."
The key to the drug's potency lies in its unusual mode of action, Shapiro said.
"BHPI works through the estrogen receptor protein, but in a way that is different than estrogenic hormones," he said. "The drug hyperactivates a pathway called the unfolded protein response, which estrogens normally use to protect cells from stress and help them grow."
Rather than blocking the stress response, BHPI kicks the UPR into overdrive, said M.D./Ph.D. student and lead author Neal Andruska.
"This drives the cancer cells from using the UPR in a protective way into making it a lethal pathway," Andruska said. "In this way, it stops growth and eventually kills many types of breast, ovarian and endometrial cancer cells that contain estrogen receptor."
BHPI shuts down the production of new proteins, including proteins that normally keep the stress response pathway in check, Andruska said.
"Eventually, many cancer cells die - in part because they can't make any new proteins," he said.
BHPI spurs a number of events in the cell, including the opening of calcium channels in the endoplasmic reticulum, a special intracellular compartment. The influx of calcium into the cytoplasm sets off a cascade of events that prepare the cell to deal with stress. The cells try to pump the calcium back into its compartment, but BHPI keeps the calcium channels open, allowing the calcium to flow back into the cytoplasm. After about 30 minutes of this "futile cycle," the cells run low on energy.
This video is not supported by your browser at this time.
Watch a movie of cancer cells responding to estrogen and BHPI.
"Without enough energy, cancer cells don't grow," Shapiro said. The cascade initiated by BHPI eventually turns on four pathways, "each of which could potentially contribute to the death of the cancer cells," he said.
Because the UPR pathway is overexpressed in therapy-resistant cancer cells, the drug is especially effective in targeting estrogen receptor-positive cells that are resistant to tamoxifen and other anti-cancer drugs, the researchers report.
"BHPI works equally well in the presence or absence of estrogen," Shapiro said.
The mice that received the drug tolerated it well, with no weight loss or other negative side effects, the researchers said.
"It's still in the early days for this drug, and there are many hurdles to overcome to bring BHPI to the clinic," Shapiro said. "But so far, it's been clearing the hurdles by a wide margin."
Explore further: Scientists discover a new role for estrogen in the pathology of breast cancer
More information: Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression, PNAS, http://ift.tt/1DlIeOg
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An experimental drug, BHPI, binds to the estrogen receptor and disrupts the growth of cancer cells. Credit: Neal Andruska
An experimental drug rapidly shrinks most tumors in a mouse model of human breast cancer, researchers report in the Proceedings of the National Academy of Sciences. When mice were treated with the experimental drug, BHPI, "the tumors immediately stopped growing and began shrinking rapidly," said University of Illinois biochemistry professor and senior author David Shapiro. "In just 10 days, 48 out of the 52 tumors stopped growing, and most shrank 30 to 50 percent."
The key to the drug's potency lies in its unusual mode of action, Shapiro said.
"BHPI works through the estrogen receptor protein, but in a way that is different than estrogenic hormones," he said. "The drug hyperactivates a pathway called the unfolded protein response, which estrogens normally use to protect cells from stress and help them grow."
Rather than blocking the stress response, BHPI kicks the UPR into overdrive, said M.D./Ph.D. student and lead author Neal Andruska.
"This drives the cancer cells from using the UPR in a protective way into making it a lethal pathway," Andruska said. "In this way, it stops growth and eventually kills many types of breast, ovarian and endometrial cancer cells that contain estrogen receptor."
BHPI shuts down the production of new proteins, including proteins that normally keep the stress response pathway in check, Andruska said.
"Eventually, many cancer cells die - in part because they can't make any new proteins," he said.
BHPI spurs a number of events in the cell, including the opening of calcium channels in the endoplasmic reticulum, a special intracellular compartment. The influx of calcium into the cytoplasm sets off a cascade of events that prepare the cell to deal with stress. The cells try to pump the calcium back into its compartment, but BHPI keeps the calcium channels open, allowing the calcium to flow back into the cytoplasm. After about 30 minutes of this "futile cycle," the cells run low on energy.
This video is not supported by your browser at this time.
Watch a movie of cancer cells responding to estrogen and BHPI.
"Without enough energy, cancer cells don't grow," Shapiro said. The cascade initiated by BHPI eventually turns on four pathways, "each of which could potentially contribute to the death of the cancer cells," he said.
Because the UPR pathway is overexpressed in therapy-resistant cancer cells, the drug is especially effective in targeting estrogen receptor-positive cells that are resistant to tamoxifen and other anti-cancer drugs, the researchers report.
"BHPI works equally well in the presence or absence of estrogen," Shapiro said.
The mice that received the drug tolerated it well, with no weight loss or other negative side effects, the researchers said.
"It's still in the early days for this drug, and there are many hurdles to overcome to bring BHPI to the clinic," Shapiro said. "But so far, it's been clearing the hurdles by a wide margin."
Explore further: Scientists discover a new role for estrogen in the pathology of breast cancer
More information: Estrogen receptor α inhibitor activates the unfolded protein response, blocks protein synthesis, and induces tumor regression, PNAS, http://ift.tt/1DlIeOg
Medical Xpress on facebook
Related Stories
Scientists discover a new role for estrogen in the pathology of breast cancer
Scientists have discovered a previously unknown mechanism by which estrogen prepares cells to divide, grow and, in the case of estrogen-positive breast cancers, resist cancer drugs. The researchers say the ...
Team discovers new inhibitors of estrogen-dependent breast cancer cells
Researchers have discovered a new family of agents that inhibit the growth of estrogen-dependent breast cancer cells. The finding, described today at a meeting of the Endocrine Society, has opened an avenue of research into ...
Control switch that modulates cell stress response may be key to multiple diseases
Researchers at the University of California, San Diego School of Medicine have discovered a control switch for the unfolded protein response (UPR), a cellular stress relief mechanism drawing major scientific interest because ...
Resistance to anti-estrogen therapy in breast cancer due to natural cell response
Most breast cancers are fueled by estrogen, and anti-estrogenic agents often work for a time to control the cancers. But many of these cancers become resistant to the drugs for reasons that are not understood, leaving patients ...
Chinese herbal extract may help kill off pancreatic cancer cells
A diagnosis of pancreatic cancer—the fourth most common cause of cancer death in the U.S.—can be devastating. Due in part to aggressive cell replication and tumor growth, pancreatic cancer progresses quickly and has a ...
Recommended for you
To stop cancer: Block its messages
The average living cell needs communication skills: It must transmit a constant stream of messages quickly and efficiently from its outer walls to the inner nucleus, where most of the day-to-day decisions ...
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Researchers in the Hereditary Endocrine Cancer Group of the Spanish National Cancer Research Centre (CNIO)—led by Alberto Cascón and Mercedes Robledo—have described the presence of mutations in the MDH2 ...
Early stage NSCLC patients with low tumor metabolic activity have longer survival
Low pre-surgery uptake of a labeled glucose analogue, a marker of metabolic activity, in the primary tumor of patients with stage I non-small cell lung cancer (NSCLC) is associated with increased overall survival and a longer ...
Researchers develop new potential drug for rare leukemia
Researchers at the University of Michigan Comprehensive Cancer Center have developed a new drug that shows potential in laboratory studies against a rare type of acute leukemia. And additional studies suggest ...
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