Aug. 9 (UPI) — Arsenic in combination with an existing leukemia drug successfully targeted the disease in mice, and offers hope of new treatment for diverse types of cancer, according to a study.
Researchers at Beth Israel Deaconess Medical Center’s Cancer Center found that arsenic trioxide, or ATO, when used in combination with all-trans retinoic acid was effective against acute promyelocytic leukemia, or APL. The findings were published Wednesday in the journal Nature Communications.
“It’s gratifying to see this combination of all-trans retinoic acid and arsenic trioxide that my lab discovered to be curative in the treatment of acute promyelocytic leukemia translate into possible approaches for the treatment of other cancers,” Dr. Pier Paolo Pandolfi, director of the hospital’s Cancder Center, said in a press release. “Indeed, it is interesting to speculate that this combination may even prove curative in other tumor types yet to be discovered.”
ATO, an oxide of arsenic, was approved by the U.S. Food and Drug Administration in 1995. Although it is known as poison, for centuries it has been used as a treatment for ailments ranging from infection to cancer before radiation and chemotherapy.
Although it has been linked to a variety of cancers in certain levels in public drinking water, its presence at other doses has been associated with unusually low rates of breast cancer.
“Our discovery strongly suggests an exciting new possibility of adding arsenic trioxide to existing therapies in treating triple-negative breast cancer and many other cancer types, especially when patients’ cancers are found to be Pin1-positive,” Dr. Xiao Zhen Zhou, an investigator in the Cancer Research Institute at BIDMC, said. “This might significantly improve the outcomes of cancer treatment.”
Although the combination was effective against APL, the researchers said it had not been fully clear what cellular targets these drugs act on, how they interact or if they might be effective against other types of cancer.
But researchers found a way in which arsenic trioxide and all-trans retinoic acid work together to combat cancer by destroying Pin1, a unique enzyme that the researchers discovered more than 20 years ago.
In clinically safe doses, the drugs inhibited numerous cancer-driving pathways and eliminated cancer stem cells in cell and animal models as well as patient-derived tumor models of triple-negative breast cancer.
Pin1 activates more than 40 cancer-driving proteins and inactivates more than 20 tumor suppressing ones as a master regulator of cancer signaling networks.
It is especially active in cancer stem cells — a subpopulation believed to drive tumor initiation, progression and metastasis.
The researchers found that arsenic trioxide fights cancer by binding, inhibiting and degrading Pin1.
Mice without Pin1 are highly resistant to developing cancer even when their cells overexpress oncogenes or lack tumor suppressors. In addition, these animals displayed no obvious defects for over half their lifespan.
Because aggressive tumors are often resistant to targeted therapies aimed at blocking individual pathways, targeting Pin1 would short circuit numerous cancer-promoting signals, and eliminate cancer stem cells, the two major sources of cancer drug resistance.
At this time no effective Pin1 inhibitors have yet been developed.
“We and others have confirmed the ability of all-trans retinoic acid to inhibit Pin1 function in breast cancer, liver cancer and acute myeloid leukemia, as well as in lupus and asthma,” Lu said. “However, clinical uses of all-trans retinoic acid, especially in solid tumors, have been severely limited by its very short half-life of 45 minutes in humans.”
The researchers said their work shows their method stimulates the development of longer half-life all-trans retinoic acid to combine with arsenic trioxide or other more potent Pin1 inhibitors “because they may offer a promising new approach to fighting a broad range of cancers without general toxicity, as proven in curing APL.”
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