Managing Editor: Steve Mason, Ph.D.
DIABETES AND LEUKEMIA: MEETING AT THE CROSSROADS
By Behzad Kharabi-Masouleh, M.D.
Diabetes mellitus Type 2 (DM2) is a chronic and progressive metabolic disease defined by the presence of uncontrolled glucose levels. It is also a leading cause for chronic kidney and cardiovascular disease worldwide (1), and current approaches for controlling DM2 aims to regulate glucose levels with the use of anti-diabetic drugs (2). Although DM2 is an already well-characterized as a risk factor for mortality, recent evidence has suggested a new role for DM2 in promoting carcinogenesis (3,4). However, these findings are perhaps not too surprising since Otto Warburg described in the 1920s several important and unique features of cancer cell metabolism that show similarities with DM2 (5).
On the other hand, leukemias, particularly acute lymphoblastic leukemia (ALL), differ greatly from solid tumors, meaning that the important pathways that play a role in driving solid tumors may not be as critical for leukemias (6). Therefore, it’s very important to understand the metabolism of leukemia cells, which could be targeted in patients whose leukemia has become resistant to other therapies. In line with this, a recent article by Pan et al. describes a novel role for insulin (a metabolic hormone) and the therapeutic potential of anti-diabetic drugs like AMPK activators, metformin and rosiglitazone in ALL (7).
First, in a series of laboratory assays, the authors probed the stimulatory effects of insulin on primary ALL cases harboring different chromosomal rearrangements, including the well-known TEL/AML1 and BCR-ABL1 rearrangements that correlate with high risk and poor outcome in ALL patients (8,9,10). While insulin and insulin analogs stimulated leukemia cell growth, anti-diabetics had an opposite effect. Mechanistically, the authors provided evidence that these effects were mediated through the insulin-induced activation of two pathways that promote cell survival and are driven by the proteins AKT and mTOR. Anti-diabetics achieved the opposite effect, and additionally increased levels of the anti-proliferative protein PTEN. A second question of clinical potential and relevance was answered when insulin protected the cells from chemotherapy while a dual treatment of chemotherapy and anti-diabetic drugs was additively toxic to cells.
Although the findings of Pan et al. are highly novel and shed a new light on insulin and anti-diabetics, the discussion still remains controversial. These results are supported by other studies (11) that show that activators of the AMPK protein (e.g. metformin) have anti-leukemic effects. This is also the case for leukemias that are resistant to tyrosine kinase inhibitors (TKIs), a class of anti-leukemic drugs. However, it is important to realize that the pathway driven by the AMPK protein can have the opposite effect, namely promoting tumor cell survival through alternative pathways (12). Therefore, it seems possible that AMPK-activators like metformin could promote tumor growth instead of inhibiting it. How can this controversy be explained?
The nature of this current controversy is rooted in our understanding of pathway studies that often follow a one-dimensional approach and do not always consider the plasticity of signaling pathways. For this specific pathway, it is important to consider that activation of AMPK may not only lead to short-term anti-leukemic effects, but it may also activate secondary tumor cell pro-survival pathways and thereby in the long run counteract the initial attempt to eliminate leukemia cells. Therefore both effects would lead to similar results, namely promoting leukemia growth. While these scenarios are hypothetical, the current results suggest that a more balanced approach could be beneficial, and that targeting an entire pathway network may be necessary to eradicate leukemia or tumor cells. This more balanced approach is also suggested by a recent clinical trial that found that although insulin itself can control glucose levels during chemotherapy, it may not always be associated with improved overall survival. In fact, this failure to improve survival led to the termination of this trial (13), providing further evidence that modulating metabolic pathways is a complex ideal that requires further research.
Behzad Kharabi Masouleh, M.D., is a physician-scientist with a major interest in translational research in oncology. He is currently a postdoctoral fellow at Children's Hospital in Los Angeles.
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