N-linked glycosylation interference and glycolysis disruption both contribute to the anticancer properties of 2-DG in breast cancer cells.

The existence of unresponsive tumors and the appearance of resistant tumors during the course of treatments both justify that we increase urgently the panel of pharmacological molecules able to fight cancer. An interesting strategy is drug reprofiling (also known as drug repositioning, drug repurposing or drug retasking) that consists of identifying and developing new uses for existing drugs. This review illustrates drug reprofiling with troglitazone (TGZ), a synthetic PPARγ agonist initially used for the treatment of type II diabetes. The fact that TGZ also displays anticancer effects is known since the end of the nineties but its development as an anticancer agent was slowed down due to hepatotoxic side effects. Part of the knowledge available for TGZ, mainly the molecular basis for PPARγ activation, its metabolization pathways and the side effects on hepatocytes, were taken into account to elaborate new molecules. Key findings were that unsaturated TGZ derivatives, when compared to TGZ, do not activate PPARγ, exhibit a higher efficiency on cancer cells and a lower toxicity towards hepatocytes. However, a weakness is that the mechanisms involved in the anticancer effects are still not completely understood and that the efficiency of such derivatives has not yet been completely studied in vivo. Data about this point should become available very soon from animal models and this will be a prerequisite to initiate clinical trials with these potential new anticancer drugs developed from a drug repurposing strategy.

The CO2 diffusion conductance within the leaf mesophyll (gm) is considered a major limiting factor of photosynthesis. However, the effects of the major secondary air pollutant ozone (O3) on gm have been poorly investigated. Eight genotypes of the economically important tree species Populus x canadensis Moench were exposed to 120 ppb O3 for 21 days. gm showed a genotype-dependent response to O3-induced oxidative stress and was a major limiting factor of the net assimilation rate (Anet), ahead of stomatal conductance to CO2 (gsc) and of the maximum carboxylation capacity of the Rubisco enzyme (Vcmax) in half of the tested genotypes. An increased leaf dry mass per area (LMA) and a decreased chlorophyll content were linked to the observed gm decrease, but this relationship did not entirely explain the different genotypic gm responses. Moreover, the oxidative stress defence metabolites ascorbate and glutathione were not related to O3-tolerance of gm. However, malondialdehyde (MDA) probably mitigated the observed gm decrease in some genotypes due to its oxidative stress signalling function. The large variation of gm suggests different regulation mechanisms amongst poplar genotypes under oxidative stress.

We have previously shown that D2-Troglitazone (D2-TGZ) displayed anticancer effects on breast cancer cell lines grown in low serum conditions (1% fetal calf serum (FCS)). The present study was performed in order to characterize the effects of D2-TGZ in high serum containing medium and to determine if starvation could influence the response of breast cancer cells to this compound, keeping in mind the potential interest for breast cancer therapy. We observed that in high serum conditions (10% FCS), a 48 h treatment with D2-TGZ induced a decrease in cell numbers in MDA-MB-231 and MCF-7 breast cancer cell lines. The IC 50 values were higher than in low serum conditions. Furthermore, in contrast to our previous results obtained in 1% FCS conditions, we observed that in 10% FCS-containing medium, MCF-7 cells were more sensitive to D2-TGZ than MDA-MB-231 cells. D2-TGZ also induced endoplasmic reticulum (ER) stress mainly in MDA-MB-231 cells. Besides, in high serum conditions, D2-TGZ induced a G 0 /G 1 cell cycle arrest, an inhibition of BrdU incorporation and a reduced level of cyclin D1. We observed a limited cleavage of PARP and a limited proportion of cells in sub-G 1 phase. Thus, in high serum conditions, D2-TGZ displayed cytostatic effects rather than apoptosis as previously reported in 1% FCS-containing medium. Our results are in accordance with studies suggesting that serum starvation could potentiate the action of diverse anti-cancer agents.

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