Fat Cells May Inactivate Chemotherapeutic Drug and Contribute to Poorer Survival in ALL
It is well established that obesity increases the risk for cancer mortality, although no mechanisms have been proven to explain the reason for this association. Now a laboratory study investigating how obesity might alter the effectiveness of daunorubicin in the treatment of acute lymphoblastic leukemia (ALL) is providing some clues. The study has found that adipocytes may metabolize and inactivate daunorubicin, reducing the active drug concentration in the tumor microenvironment and potentially contributing to poorer survival outcomes. The study’s finding could help explain why cancer patients with obesity are at risk of having a poorer outcome than their leaner counterparts and may have important implications across many diseases. The study by Sheng et al was published in Molecular Cancer Research.
Study Methodology
The researchers co-cultured human ALL cell lines with adipocytes and treated them with daunorubicin. They also studied whether human adipose tissue from patients with cancer, including adipose tissue biopsy samples from breast cancer survivors and bone marrow biopsy specimens from children aged 10 to 21 with high-risk ALL, could metabolize daunorubicin.
The researchers measured the presence of daunorubicin through flow cytometry and liquid chromatography/mass spectrometry and examined fat cells in bone marrow from the children with ALL.
Study Findings
The researchers made several key findings:
- The presence of adipocytes significantly reduced the accumulation of daunorubicin in the ALL cells;
- The adipocytes absorbed the chemotherapeutic agent, removing it from the leukemia environment. The leukemia cells treated with daunorubicin survived and proliferated better in samples that contained adipocytes;
- The adipocytes metabolized daunorubicin. Enzymes in the fat cells changed the structure of the chemotherapy molecule, making it much less toxic to the leukemia cells.
“Specifically, adipocytes metabolize daunorubicin to a less toxic metabolite and allow nearby ALL cells to evade daunorubicin-induced cytotoxicity. This finding could help explain why obese cancer patients are at risk of having a poorer outcome. Pharmacokinetic studies specifically in the tumor microenvironment will be necessary to determine the precise impact of adiposity on anthracycline-based treatment and efficacy in patients with ALL and other cancers,” concluded the study authors.
“The finding that human fat cells can metabolize and inactivate a chemotherapy is novel and surprising,” said Steven Mittelman, MD, PhD, Associate Professor of Pediatrics and the Division Chief of Pediatric Endocrinology at UCLA Mattel Children’s Hospital in Los Angeles, and a coauthor of this study, in a statement. “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.”
Funding for this study was provided by the National Cancer Institute, The Saban Research Institute, the Leukemia & Lymphoma Society, the V Foundation for Cancer Research, and the National Center for Advancing Translational Science of the National Institutes of Health.
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®.
