Taking a leukemia chemotherapy drug may help breast cancer patients who don't respond to tamoxifen overcome resistance to the widely-used drug, new research from the Kimmel Cancer Center at Jefferson suggests.
Interestingly, researchers found that tamoxifen combined with dasatinib, a protein-tyrosine kinase inhibitor, reverses the chemo-resistance caused by cancer-associated fibroblasts in the surrounding tissue by normalizing glucose intake and reducing mitochondrial oxidative stress, the process that fuels the cancer cells.
Previous animal studies have confirmed that combining tyrosine kinase inhibitors with anti-estrogen therapies, like tamoxifen, can prevent drug resistance, but none have suggested that the target of the inhibitors is the cancer-associated fibroblasts.
The researchers report their findings in the August 1 issue of Cell Cycle.
About 70 percent of women diagnosed with breast cancer will have estrogen receptor positive (ER(+)) disease, which indicates that the tumor may respond to tamoxifen. However, a large percentage of these tumors—up to 35 percent—have little to no response to the drug or eventually develop resistance to it.
In this study, researchers sought to better understand drug resistance by looking at the metabolic basis in an ER (+) cell line and cancer-associated fibroblasts. The researchers have previously established a relationship between the two, where cancer cells induce aerobic glycolysis by secreting hydrogen peroxide in adjacent fibroblasts via oxidative stress. In turn, these fibroblasts provide nutrients to the cancer cells to proliferate, a process that ultimately makes tumors grow.
Here, they investigated and then demonstrated that this interaction was also the basis of tamoxifen resistance.
In a sense, the drug combination had an "antioxidant effect" in these types of cancer cells, according to Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology and Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center.
"The fibroblasts are what make ER (+) cancer cells resistant to the tamoxifen," said Dr. Lisanti. "But the tamoxifen plus dasatinib maintained both fibroblasts and cancer cells in a 'glycolytic state,' with minimal oxidative stress and more cell death, most likely because of an absence of metabolic coupling. The supply between the two was cut."
"This suggests resistance to chemotherapeutic agents is a metabolic and stromal phenomenal," he added.
Researchers showed that ER (+) cancer cells alone responded to tamoxifen but when co-cultured with human fibroblasts had little to no effect. Similarly, dasatinib, a chemotherapy drug used to treat leukemia patients who can no longer benefit from other medications, had no effect on fibroblasts alone or cancer cells. Together, however, the drugs prevented the cancer cells co-cultured with the fibroblasts from using high-energy nutrients from the fibroblasts.
This combination resulted in nearly 80 percent cell death, the team reported—a two to three fold increase when compared with tamoxifen alone.
"The drugs have no effect when they are used alone—it's in unison when they effectively kill the cancer cells in the presence of fibroblasts," said Dr. Lisanti. "This opens up the door for possible new treatment strategies. This 'synthetic lethality' may help patients overcome resistance in the clinic."
Steve Graff | EurekAlert!
NTU scientists build new ultrasound device using 3-D printing technology
07.12.2016 | Nanyang Technological University
How to turn white fat brown
07.12.2016 | University of Pennsylvania School of Medicine
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
07.12.2016 | Health and Medicine
07.12.2016 | Life Sciences
07.12.2016 | Health and Medicine