Researchers Uncover How a Potent Compound Kills Prostate Cancer Cells
A new study led by researchers at Sanford-Burnham Medical Research Institute reveals how a promising anticancer compound called SMIP004 specifically kills prostate cancer cells by compromising their ability to withstand environmental stress. The study, recently published in Oncotarget, uncovered novel mechanisms of anticancer activity and could lead to the development of more effective therapies for advanced and hard-to-treat forms of prostate cancer, as well as other types of cancer.
“For advanced prostate cancer—castration-resistant prostate cancer, in particular—when the cancer recurs, the only therapy is [paclitaxel], which will prolong life for only a couple of months,” said senior study author Dieter Wolf, MD, Director of the National Cancer Institute–designated Cancer Center proteomics facility at Sanford-Burnham. “There’s good potential that our compound could become a novel, much-needed therapy for castration-resistant prostate cancer.”
New Compound, New Mechanisms
In a previous study, Dr. Wolf and his team identified SMIP004 as a promising anticancer agent when they screened for compounds that specifically kill prostate cancer cells while sparing normal cells. But until now, exactly how SMIP004 works was unknown.
In the new study, the researchers found that SMIP004 causes cancer cells to die by interfering with the functioning of mitochondria. During oxidative stress, reactive oxygen species (ROS) built up within mitochondria, causing the cells to stop replicating and to start dying. Dr. Wolf and his team pinpointed the exact molecular signaling pathways underlying SMIP004’s effects and identified ROS-mediated activation of the unfolded protein response as the trigger of cancer-cell death. “I’m not aware of any approved drugs with the mechanism of action we identified,” Dr. Wolf said.
Through one of the newly identified pathways triggered by oxidative stress, SMIP004 caused a decrease in the number of androgen receptors. In patients with castration-resistant prostate cancer, cancer cells develop the ability to use low levels of testosterone for survival by increasing the production of androgen receptors. “Because SMIP004 acts on the androgen receptor, it is particularly promising for castration-resistant prostate cancer,” Dr. Wolf said.
Targeting Cancer Cells
Moreover, the researchers found that SMIP004 strongly inhibited the growth of prostate and breast cancer in mice, underscoring the compound’s potential value in treating a range of cancers. All types of cancer cells are exposed to stressful conditions, including high levels of oxidative stress resulting from the activation of cancer-causing genes. SMIP004 increased mitochondrial ROS levels by 40%, which was enough to tip these cells over the edge and cause them to die.
“The compound increases the stress level beyond what a cancer cell can take, whereas normal cells can cope with it because they have a much lower level of oxidative stress to begin with,” Dr. Wolf said. “So we think that SMIP004 is likely to be harmless to normal cells, but broadly effective against many types of cancer cells.”
This research was funded by grants from the National Institutes of Health and by the U.S. Department of the Army, and by a Prostate Cancer Training Award.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
