metformin is synthetically lethal (kills in combination with) glucose deprivation in

[Lani]

cancer cells, especially her2+ breast cancer cells

It appears the concentration of metformin that might be needed to kill the cells is higher than is safe in people, unless you also deplete their glucose. Perhaps a few treatments might do it in theory it would seem to me, purging the system of all cancer stem cells.

Here are comments on the new article:

Comment on: Menendez JA, et al. Cell Cycle 2012; 11: In this issue.



In a recent issue of Cell Cycle, Menendez and colleagues proposed a novel concept, that metformin is synthetically lethal with glucose withdrawal in cancer cells.1 Historically, synthetic lethality has focused on how tumor cells are responsive to certain agents that only harbor specific constitutive epigenetic or genetic lesions.2 More recent data from several groups have uncovered that altered tumor microenvironment could be used to confer synthetic lethality to specific drugs, defined as “contextual synthetic lethality,” that is microenvironment-mediated. For example, hypoxia-induced HR (homologous repair) defect has been shown to be synthetically lethal to PARP inhibition, while PARP inhibition, per se, did not alter HR inhibition or function, thus providing a prime example of “contextual synthetic lethality.”3 In this report, Menendez et al. have elegantly connected the glucose-deprived tumor microenvironment in primary tumors as a synthetic lethal partner to metformin. Metformin is a FDA-approved drug to treat diabetic patients that is gaining momentum as a repurposing drug for cancer treatment.4 Using several different breast cancer cells with and without oncogenic activation, the authors have shown that the glucose-rich conditions of the in vitro experiments dictates the use of very high concentrations of metformin, which are not applicable to glucose-starved in vivo conditions. While other reports have alluded to the effect of glucose withdrawal in killing genetically compromised cells to therapeutic effect of metformin in vitro,5 Menendez et al have provided a logical explanation for the use of very high concentrations of metformin to achieve anticancer effects in vitro in the high glucose-rich environment used in these experiments, which are clinically not applicable in vivo in patients.

Based on these findings, it can be envisaged that in the tumor microenvironment, where the cancer cells are under extreme nutritional and hypoxic stress (a niche for cancer stem cells), metformin treatment could favor synthetic lethality and hence effectively can attenuate tumor growth. The tumor microenvironment thus enables the bioenergetic switch in favor of glycolysis and dependence on glucose and glutamine as a rapid source of nutrition. While the authors’ data clearly depicts how metformin eliminates the tolerance of the breast cancer cells to fluctuations in glucose concentrations, it is important to understand how the availability of other dominant sources of energy, such as glutamine, might participate in this scenario. It is plausible that subtype of breast cancers, i.e., basal vs luminal, might depend on different energy sources, albeit to a different extent.6 This is important, because tumor cells often acquire metabolic adaptability toward available preferred energy source to adapt well to nutritional stress via autophagy and altered metabolism.7 Along these lines, the authors rationalize the therapeutic targeting of the cancer stem cells by metformin through its synthetic lethal activity to the hyperglycotic phenotype often seen in CSC to sustain their stemness.8 Further characterization of how metformin treatment alters the metabolic nodes in cancer stem cells and/or p53-null cells would explain the underpinning mechanisms for increased susceptibility of these indolent and aggressive cancer cells toward metformin.

It is well documented that metformin, by inhibiting complex I of respiratory chain in mitochondria (ETCI), induces a decrease in the ATP levels, and that glucose depletion also decreases ATP levels, albeit to varying levels. Therefore, it is possible that simultaneous targeting of both pathways (glycolytic pathway and OXPHOS) caused ATP depletion below a critical threshold, resulting in cell death. This concept is supported by the elegant study9 highlighting the effectiveness of combination of glycolysis inhibition by 2-DG and metformin in several preclinical models exhibiting anti-tumor effects, including MB-MDA231 used in this study.

Since recent studies indicate that inhibiting glucose uptake with small-molecule inhibitors led to a decline in cylcin E2 and p-RB levels,10 it is a possibility that cell cycle inhibitor levels are also regulated under glucose withdrawal conditions, sensitizing cells to cytotoxic effects of metformin in breast cancer cells.

Considering data from several studies, a view that metformin treatment has pleotropic effects on several signaling pathways under glucose-free conditions seems a practical possibility. Overall, this work offers several new insights into glucose-dependent mechanisms underpinning the mode of action of metformin as a viable therapeutic strategy.