The association of hyperglycemia with outcomes in ALL patients is multifactorial. Factors such as an altered metabolism that supports the proliferative state of leukemic cells23
and impaired immune function24
may contribute to early relapse. Hyperinsulinemia and increased levels of IGF-1 have also been shown to promote tumor growth in solid tumors.25-27
Recently we demonstrated that different types of anti-diabetic pharmacotherapy had a differential direct impact on breast and pancreatic cancer cells.28
Here, we have found evidence that the engineered insulin analogs (aspart and glargine) may stimulate proliferation of ALL cells to a greater degree than regular human insulin.
The impact of glargine on cancer is highly controversial. A cohort study raised the concern for a higher than expected incidence of cancer in patients on glargine compared with human insulin,29
but other epidemiologic studies did not corroborate the potential link to increased cancer incidence.30-33
The potential difference between glargine and human insulin on carcinogenesis and cancer incidence may need long-term (> 5 y) studies to detect convincingly.34
Some publications support that glargine stimulates malignant cell growth more than insulin,35,36
while others do not.37-40
Our data about the higher stimulatory of glargine and aspart than human insulin in ALL cells and data by others in other cancer cells35,36
would suggest that one area of future research should focus on whether cancer patients on glargine and/or aspart have worse oncologic outcomes than those on human insulin.
In addition to an indirect mechanism through the systemic effect of metformin on insulin level, metformin may suppress malignancy by direct mechanisms involving stem cell-like cancer cells, epithelial-to-mesenchymal transition (EMT) and cellular senescence.41
Metformin also suppresses malignant cells through activation of AMPK, leading to inhibition of mTOR,20,21,28,42-44
and the regulation of the FoxO3A transcriptional program by AMPK is also relevant in autophagic cell death of persistently stressed cells.45
Thiazolidinedione PPARγ ligands inhibit proliferation and induce apoptosis of cancer cells,28,46,47
and inhibit tumor angiogenesis and invasion.46,48
They attenuate signaling through the IGF-1R signaling pathway49,50
as PPARγ activation upregulates the expression of PTEN, an inhibitor of signaling through AKT/mTOR.51
Studies on aging and caner across the animal kingdom (nematodes, fruit flies and mice) suggest that elevation in glucose, insulin and IGF-1 are important factors linked to shorter lifespans and anti-insulin resistance drugs and interventions that interfere with insulin/IGF-1 signaling postpone or inhibit carcinogenesis.52
Here, in terms of malignant cell proliferation, we have demonstrated that insulin and analogs stimulate, while metformin and thiazolidinediones inhibit, ALL cells using both cell lines and primary patient samples (–). Modeling of log dose responses predicted that pharmacologically achievable concentrations of insulin and analogs (), and metformin and rosiglitazone () might have significant impact on the number live ALL cells. We have experimentally confirmed that these predicted concentrations of the anti-diabetic medications do cause statistically significant changes in the number of ALL cells. Insulin and analogs activate the AKT/mTOR signaling pathway, while metformin and rosiglitazone inhibit mTOR signaling (). Insulin and analogs induced chemoresistance to daunorubicin, while metformin and thiazolidinediones improved chemosensitivity to daunorubicin and other agents (). The chemosensitivity to anthracyclines may be regulated by the Raf/
MEK/ERK and PI3K/PTEN/Akt/mTOR pathways,53
and inhibition of the PI3K/PTEN/Akt/mTOR pathway can enhance chemosensitivity. Chemosensitivity to other agents (etoposide, vincristine, L-asparaginase and methotrexate) showed varied responses, which suggests that the pathways or mechanisms regulating chemosensitivty to these other agents are different from those for anthracyclines. Taken together, all these data support the notion that insulin and analogs are detrimental, while metformin and thiazolidinediones are beneficial, to the clinical outcomes of hyperglycemic ALL patients undergoing hyper-CVAD chemotherapy.
In contrast to cycled/pulsed treatment with classical cytotoxic chemotherapy that results in high percentages of malignant cells being killed, chronic inhibitory/suppressive therapy, which may have some similarity to metronomic therapy,54
will only need a very modest impact to translate into clinically meaningful benefits over the long-term. For example, a mere 2.5% decrease in the number of cancer cells by a drug compared with control observed in 3 d may become a 53.2% decrease in tumor burden in 3 mo (i.e., 0.97530
= 0.468). Antidiabetic pharmacotherapy involves chronic administration; modest short-term impact on malignant cells at normal human doses will become clinically significant over time. The effects of insulin or analogs compared with the opposite effects of metformin or thiazolidinediones on malignant cells will magnify the difference. A caveat for this argument is the possibility of tachyphylaxis (i.e., the antidiabetic drugs may stop having an effect on malignant cells after many days of exposure). However, epidemiologic evidence does not support this caveat, and diabetic patients with various types of cancer have different prognoses associated with the anti-diabetic drugs they use.55-57
An epidemiologic study revealed an increased risk of cancer-related death in diabetic patients treated with sulfonylureas and insulin preparations than in those treated with metformin,58
and based on our previous results in reference 12
and results reported in this paper, this difference is very likely due to both detrimental effects of insulin preparations and the beneficial effect of metformin on cancer cell growth and chemoresistance. Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher complete response rate than do diabetics not receiving metformin.59
This epidemiologic evidence and our finding that metformin adds to the cytotoxic effect of daunorubicin corroborate each other. Specifically for hyperglycemic ALL patients undergoing hyper-CVAD chemotherapy, a randomized clinical trial comparing intensive insulin therapy using glargine and aspart with conventional therapy (control) was terminated early because of a trend that survival in the intensive insulin therapy arm was worse than the control arm and a probability of 0.0001 to conclude in favor of the intensive insulin therapy arm.60
Secondary analysis of the data in this clinical trial suggests that exogenous insulin may be associated with poor outcomes, while metformin and thiazolidinediones may be associated with improved outcomes.60
The results in this paper and the results of our clinical trial corroborate one another.
To our knowledge, this is the first study that includes evidence from primary leukemic patient samples to demonstrate that insulin and insulin analogs are associated with a high proliferation rate and chemoresistance, while metformin and thiazolidinediones are associated with low proliferation rate, apoptosis and chemosensitivity of ALL cells. While we need to learn more about the interactions of anti-diabetic pharmacotherapy with malignancies and their response to treatments, future research should also seek confirmation of beneficial effects of biguanides and thiazolidinediones to the clinical outcomes of malignant diseases in prospective trials. Our results open the avenue to potentially influence the clinical outcomes and survival of hyperglycemic ALL patients simply by making an informed choice of anti-diabetic pharmacotherapy. The implications of our data may reach beyond the context of hyperglycemic ALL patients to normoglycemic patients. Currently, a phase III adjuvant trial (NCIC MA.32) is investigating the addition of metformin to chemotherapy for breast cancer.61
In low glucose culture conditions, a combination of rapamycin and metformin kills cancer cells without killing normal cells;62
these results, taken together with our findings, suggest that the combination of metformin and an mTOR inhibitor may have a wide therapeutic window. We are currently evaluating this idea of combining metformin with an mTOR inhibitor (everolimus) in a clinical trial of obese and overweight postmenopausal patients with metastatic hormone-responsive breast cancer on exemestane therapy. The safety of metformin and thiazolidinediones in normoglycemic patients and their chemosensitizing effects may justify clinical trials to evaluate the addition of metformin and/or thiazolidinediones to chemotherapy for ALL.