New Drug Stalls Cancer Cell Growth And Shrinks Tumors

New Drug Stalls Cancer Cell Growth And Shrinks Tumors
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", the researchers said. "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. BHPI works through the estrogen receptor protein, but in a way that is different than estrogenic hormones. 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. This drives the cancer cells from using the UPR in a protective way into making it a lethal pathway. 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. Eventually, many cancer cells die - in part because they can't make any new proteins.

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. Without enough energy, cancer cells don't grow. The cascade initiated by BHPI eventually turns on four pathways, each of which could potentially contribute to the death of the cancer cells.
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. The mice that received the drug tolerated it well, with no weight loss or other negative side effects.
Below is a movie of cancer cells responding to estrogen and BHPI.

Based on material originally posted by University of Illinois at Urbana-Champaign.