Fat Cells Inactivate Cancer Chemotherapy

Obesity is linked with poorer outcomes for patients with a range of cancers, including breast, colon, ovarian, and prostate. The results from new studies now indicate that fat cells in a tumor microenvironment (TME) can directly take up and metabolize at least one type of chemotherapy and so prevent the active drug from reaching and killing the cancer cells.

“The finding that human fat cells can metabolize and inactivate a chemotherapy is novel and surprising,” says the study’s lead scientist Steven Mittelman, M.D., Ph.D., associate professor of pediatrics and the division chief of pediatric endocrinology at UCLA Mattel Children’s Hospital in Los Angeles. “This is important for leukemia and a lot of other cancers that grow in the bone marrow or around fat cells, since that means that fat cells might remove chemotherapy from the environment and allow the cancer cells to survive.”

Research has suggested that excess fat affects how chemotherapy drugs are absorbed and metabolized. Past studies by Dr. Mittelman’s lab have also shown that adipocytes can protect acute lymphoblastic leukemia (ALL) cells from the anthracycline chemotherapy agent daunorubicin. To see whether fat cells are directly responsible for clearing the drug from the tumor microenvironment, the researchers cocultured ALL cell lines with adipocytes and treated the culture with the chemotherapeutic. Using techniques including flow cytometry, liquid chromatography/mass spectrometry, and quantitative polymerase chain reaction (qPCR), the team measured levels of daunorubicin, together with its largely inactive metabolite, and the expression of daunorubicin-metabolizing enzymes, in cultured cells and also in human tissues, including fat cells from the bone marrow of children with leukemia.

The results showed that adipocytes markedly blocked the accumulation of daunorubicin in the ALL cells. The fat cells effectively absorbed the drug from the tumor microenvironment and metabolized it into the largely inactive compound daunorubicinol, which is far less toxic to leukemia cells. As a result, ALL cells treated with daunorubicin in the presence of fat cells were able to survive and proliferate. Subsequent studies in mice confirmed that the conversion of daunorubicin to daunorubicinol also occurs in adipose tissue in vivo.

These results are published in Molecular Cancer Research, in a paper entitled “Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin.”

“To our knowledge, this is the first demonstration that adipocytes metabolize and inactivate a therapeutic drug,” the researchers write. “Adipocyte-mediated daunorubicin metabolism reduces active drug concentration in the TME. These results could be clinically important for adipocyte-rich cancer microenvironments such as omentum, breast, and marrow.”

The researches say more research will be needed to find out if the presence of adipocytes has a similar effect on other types of chemotherapy and on the effectiveness of treatment on different types of cancer. “A deeper understanding of the process could lead clinicians to deliver more effective treatment by choosing or designing chemotherapy drugs that are more resistant to the enzymes in fat cells,” notes co-author Etan Orgel, M.D., M.S., attending physician at the Children’s Hospital Los Angeles, and an assistant professor of pediatrics at the Keck School of Medicine at the Unviversity of Southern California, Los Angeles.

The findings could also have implications for the treatment of many other diseases in obese patients, because the daunorucibin-metabolizing aldo-keto reductase and carbonyl reductase enzymes that are produced by human fat cells also metabolize a number of other drugs and are sometimes expressed at higher levels in obese individuals.