Chronic lymphocytic leukemia (CLL) is a type of cancer of the peripheral blood mononuclear cells (PBMC) with massive unregulated production of B cells.
Drug design for cancer incorporates molecular mechanisms that interfere with cell division or promote cell death to curb the prolific propagation of cancer-causing cells. The first challenge is unraveling the disease at the molecular level. While it is always a daunting task, for CLL it is especially complicated, for there are several mechanisms that B cells can use to bypass the checks and balances that regulate cells for controlled growth. CLL is therefore labeled as a heterogeneous disease, or one with assorted molecular mechanisms that give the end result of diseased B cells.
When diseased B cells in a CLL patient are targeted with a drug, those B cells that can bypass or escape the lethal blockade of a cellular pathway will survive. Matrix metalloproteinase-9 (MMP-9) is a protein present in the environment of B cells, as well as within B cells. When bound to receptors on B cells, MMP-9 causes cell migration and also prevents spontaneous apoptosis, or cell death.
The prevalent MMP-9 and its inherent abilities make the case for investigation. Could MMP-9 alter the effectiveness of chemotherapy drugs in CLL? This is important to investigate so that scientists can design therapeutic counter-attacks.
A group of scientists pursued research into MMP-9 and its effects on chemotherapy. They began by isolating B cells from several CLL patients. They also grew stromal cells in cell culture to mimic the microenvironment of B cells. Using molecular techniques, they converted the stromal cells in some culture flasks to express high levels of MMP-9.
Two chemotherapy drugs, arsenic trioxide (ATO) and fludarabine, were tested in the above set-up. When cells from CLL patients were cultured in the presence of ATO or fludarabine, MMP-9 was up-regulated in these cells endogenously (internally). And when MMP-9 was added to CLL cells exogenously (externally), the cells became resistant to the cytotoxic effects of ATO or fludarabine. At the molecular level, scientists found that MMP-9 induced drug resistance by modulating the balance of anti- and pro-apoptotic (cell death) proteins from the Bcl-2 family.
With the knowledge gained from this study, improvements could be made to chemotherapy agents by combining existing therapies with new drugs that target MMP-9. HemaCare provides several disease state cells for research purposes, such as those from CLL patients. We expect that the availability of disease state materials will aid in further advances in the fight against CLL.
1: Amigo-Jiménez I, Bailón E, Ugarte-Berzal E, Aguilera-Montilla N, García-Marco JA, García-Pardo A. Matrix metalloproteinase-9 is involved in chronic lymphocytic leukemia cell response to fludarabine and arsenic trioxide. PLoS One. 2014 Jun 23;9(6):e99993. 2014. PubMed PMID: 24956101.