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Nguyen et al. Cancer Drug Resist 2018;1:126-38 I http://dx.doi.org/10.20517/cdr.2018.08 Page 133

of c-myc, leading to GLS expression by repressing miR-23a/b [20,95] . Intriguingly, in an organotypic 3D tis-
sue culture model, mTORC1 supports the expression of aminotransferases and the suppression of GDH in
[96]
proliferating cells . Thus, the regulation of glutamine metabolism by mTORC1 is cell type-dependent and
needs to be elucidated further. Moreover, mTORC1 controls glutamine transporters SLC1A4 and SLC1A5
[97]
expression, thereby promoting glutamine uptake upon androgen receptor signaling in prostate cancer .
Interestingly, evidence has shown that glutamine flux through glutamine transporters activates mTOR sig-
[98]
naling .
In summary, glutamine uptake and metabolism have a tight connection with mTOR signaling. As both
pathways are upregulated in many cancers, strategies which target both glutamine metabolism and
[99]
mTORC1 signaling have shown synergistic effects against cell growth and proliferation .

THERAPEUTIC APPLICATIONS
Given the dependence of cancer cells on glutamine metabolism, targeted therapies have been developed
against glutamine metabolism, from glutamine uptake to glutamine-catalysed enzymes. The inhibition of
GLS got the attention due to the dysregulation of GLS in a variety of cancers. Indeed, GLS inhibitors have
shown promising tumor-suppressive activities in preclinical models for 968 and bis-2-(5-phenylacetamido-
1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), or even in clinical models for CB-839 [100,101] . CB-839 has shown
efficacy in triple-negative breast cancer and haematological malignancies therapies [101,102] . In addition to
GLS inhibitors, strategies targeting the conversion of glutamate into α-ketoglutarate, such as GDH inhibi-
tors and aminotransferase inhibitors, have also been evaluated in preclinical models of breast cancer and
neuroblastoma [103-105] .

Nevertheless, most of the compounds are still in the preclinical evaluation stage, or have been directly dis-
carded due to high cytotoxicity. Furthermore, some limitations derived of treatment resistance to targeted
therapies against glutamine metabolism have been reported. Induction of pyruvate carboxylase can allow
tumor cells to use glucose-derived pyruvate instead of glutamine for anaplerosis, inducing a glutamine-
independent growth [106-108] . Also, glutamate-derived glutamine production through GS activity could be
another mechanism to overcome glutamine addiction and to promote resistance to glutaminolysis inhibi-
tors . However, combination therapy between glutamine metabolism inhibitors and other pathway inhibi-
[85]
tors induced a stronger apoptotic response and enhanced anti-tumor efficacy. For instance, mTOR inhibi-
tion in glioblastoma multiforme cell lines led to a compensatory upregulation of glutamine metabolism,
promoting mTOR inhibitor resistance. Thus, combined inhibition of mTOR and GLS resulted in synergis-
tic tumor cell death and growth inhibition in xenograft mouse models .
[99]

CONCLUSION AND FUTURE PERSPECTIVES
Glutamine metabolism plays a central role in the regulation of uncontrolled tumor growth by supply-
ing metabolic intermediates as a carbon and nitrogen source and by maintaining the redox homeostasis
against oxidative stress during rapid proliferation. The high demand of cancer cells for glutamine results
in glutamine addiction phenotype, which becomes a promising target for the design of new therapeutic
strategy. Future investigations will elucidate the molecular mechanism of glutamine addiction by identify-
ing the death pathways activating during the impairment of glutamine catabolism or when glutamine is
limited. Finally, the development of an effective drug targeting glutamine metabolism is another challenge
for the development of novel anticancer therapeutic strategies.

DECLARATIONS
Authors’ contributions
Wrote the manuscript: Nguyen TL, Durán RV