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Taking a leukemia chemotherapy drug may help breast cancer patients who don't respond to tamoxifen overcome resistance to thewidely-used drug, new research from the Kimmel Cancer Center atJefferson suggests. Interestingly, researchers found that taxoxifen combined withdasatinib, a protein-tyrosine kinase inhibitor, reverses thechemo-resistance caused by cancer-associated fibroblasts in thesurrounding tissue by normalizing glucose intake and reducingmitochondrial oxidative stress , the process that fuels the cancer cells. Previous animal studies have confirmed that combining tyrosinekinase inhibitors with anti-estrogen therapies, like tamoxifen, canprevent drug resistance, but none have suggested that the target ofthe inhibitors is the cancer-associated fibroblasts. The researchers report their findings in the August 1 issue of CellCycle. About 70 percent of women diagnosed with breast cancer will haveestrogen receptor positive (ER(+)) disease, which indicates thatthe tumor may respond to tamoxifen. However, a large percentage ofthese tumors up to 35 percent have little to no response to thedrug or eventually develop resistance to it. In this study, researchers sought to better understand drugresistance by looking at the metabolic basis in an ER (+) cell lineand cancer-associated fibroblasts. The researchers have previouslyestablished a relationship between the two, where cancer cellsinduce aerobic glycolysis by secreting hydrogen peroxide inadjacent fibroblasts via oxidative stress. In turn, thesefibroblasts provide nutrients to the cancer cells to proliferate, aprocess that ultimately makes tumors grow. Here, they investigated and then demonstrated that this interactionwas also the basis of tamoxifen resistance. In a sense, the drug combination had an "antioxidant effect" inthese types of cancer cells, according to Michael P. Lisanti, M.D.,Ph.D., Professor and Chair of Stem Cell Biology and RegenerativeMedicine at Jefferson Medical College of Thomas JeffersonUniversity and a member of the Kimmel Cancer Center. "The fibroblasts are what make ER (+) cancer cells resistant to thetamoxifen," said Dr. Lisanti. "But the tamoxifen plus dasatinibmaintained both fibroblasts and cancer cells in a 'glycolyticstate,' with minimal oxidative stress and more cell death, mostlikely because of an absence of metabolic coupling. The supplybetween the two was cut." "This suggests resistance to chemotherapeutic agents is a metabolicand stromal phenomenal," he added. Researchers showed that ER (+) cancer cells alone responded totamoxifen but when co-cultured with human fibroblasts had little tono effect. Similarly, dasatinib, a chemotherapy drug used to treatleukemia 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 thefibroblasts from using high-energy nutrients from the fibroblasts. This combination resulted in nearly 80 percent cell death, the teamreported a two to three fold increase when compared with tamoxifenalone. "The drugs have no effect when they are used alone it's in unisonwhen they effectively kill the cancer cells in the presence offibroblasts," said Dr. Lisanti. "This opens up the door forpossible new treatment strategies. This 'synthetic lethality' mayhelp patients overcome resistance in the clinic." Source: Thomas Jefferson University Additional References Citations. I am an expert from hydraulic-piston-pump.com, while we provides the quality product, such as Vickers Pump , Hydraulic Pressure Valve, Hydraulic Piston Pump,and more.
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