A study conducted in April revealed that fish oil may boost responses to breast cancer drug tamoxifen. More recently, a research conducted by Kimmel Cancer Center researchers, has disclosed that a chemotherapy drug used for leukemia apparently helps breast cancer patients combat their resistance to the drug tamoxifen.
Analysts found that tamoxifen when added to dasatinib inverts the chemo-resistance due to cancer-associated fibroblasts in the ambient tissue. This is done by bringing glucose intake to normal levels and decreasing mitochondrial oxidative stress. Nearly, 70% of women tested positive for breast cancer seem to have estrogen receptor positive ER (+) disease, which shows that the tumor may react to tamoxifen. However, 35% of them have very less or no responsiveness to the medicine and in due course of time they tend to develop resistance for it. Initial studies have unfolded that combining kinase inhibitor drugs with anti-estrogen therapies like tamoxifen may lower drug resistance. Notably, inhibitors seem to target the cancer-associated fibroblasts.
The researchers planned to examine the metabolic basis in an ER (+) cell and cancer-associated fibroblasts. They have earlier presented a link between the two where cancer cells invoke glycosis by releasing hydrogen peroxide in nearby fibroblasts through a process of oxidative stress. In response, the fibroblasts deliver nutrients to cancer cells that cause tumors to expand. This was apparently the basis of tamoxifen resistance.
“In a sense, the drug combination had an “antioxidant effect” in these types of cancer cells. The fibroblasts are what make ER (+) cancer cells resistant to the tamoxifen. 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,” commented 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 analysts also showed that ER (+) cancer cells singlehandedly reacted to tamoxifen but when programmed with human fibroblasts, did not seem to have any influence. On similar lines, dasatinib, a chemotherapy drug used to treat leukemia patients, seemingly showed no result in fibroblasts or cancer cells. However tamoxifen and dasatinib seem to work efficiently as a combo to reduce the usage of high energy nutrients by cancer cells. These drugs when teamed up led to almost 80% of cell mortality that is 2 to 3 folds higher than tamoxifen alone. This research paves way for new therapies and treatment strategies. The synthetic lethality may aid cancer patients to overcome resistance at clinical level.
The research is published in the August 1 issue of Cell Cycle.