Synergistic increase in efficacy of a combination of 2-deoxy-d-glucose and cisplatin in normoxia and hypoxia: switch from autophagy to apoptosis

Jalota, Akansha; Kumar, Mrityunjay; Das, Bina Pani; Yadav, Ajay; Chosdol, Kunzang; Sinha, Subrata

doi:10.1007/s13277-016-5089-8

Cited by 24 publications

(15 citation statements)

References 34 publications

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“…More and more studies reported that increased aerobic glycolysis is a hallmark of cancer and plays a role in chemoresistance in different cancer cells [ 7 – 9 , 22 , 23 ]. To directly demonstrate if 2-DG treatment can reverse GC resistance, we incubated ALL and Raji cells with 1 mM 2-DG and/or 1 μM dexamethasone (Dex) for 24 h and 48 h. 2-DG combined with Dex inhibited the viability of GC resistant cells (Raji, Jurkat, CEM-C1-15, Molt-4) synergistically (Figure 3A ).…”

Section: Resultsmentioning

confidence: 99%

Low dose of 2-deoxy-D-glucose kills acute lymphoblastic leukemia cells and reverses glucocorticoid resistance via N-linked glycosylation inhibition under normoxia

Zhang

et al. 2017

Oncotarget

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Recent studies showed that 2-deoxy-D-glucose (2-DG), a glucose analog with dual activity of inhibiting glycolysis and N-linked glycosylation, can be selectively taken up by cancer cells and be used as a potential chemo- and radio-sensitizer. Meanwhile, 2-DG can kill cancer cells under normoxia. However, its efficacy is limited by the high-dose induced systemic toxicity. Here, we showed that low-dose 2-DG could be used as a single agent to kill acute lymphoblastic leukemia (ALL) cells, and as a GC sensitizer to overcome GC resistance under normoxia. Addition of exogenous mannose, a sugar essential for N-linked glycosylation, rescued 2-DG-treated ALL cells, indicating that inhibition of N-linked glycosylation and induction of endoplasmic reticulum stress is the main mechanism for 2-DG to induce cell death and reverse GC resistance in ALL cells. These data provides new insight into the molecular mechanisms involved in GC resistance. More important, it indicates that 2-DG might be the promising drug for designing novel high efficiency and low toxic protocol for ALL patients.

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Section: Resultsmentioning

confidence: 99%

Low dose of 2-deoxy-D-glucose kills acute lymphoblastic leukemia cells and reverses glucocorticoid resistance via N-linked glycosylation inhibition under normoxia

Zhang

et al. 2017

Oncotarget

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“…As suggested, methenamine has been successfully applied to treat central nervous system infections in the past, suggesting that it crosses through the blood–brain barrier and releases cytocidal levels formaldehyde in hypoxic tissues. In tumours, hypoxia aggravates chemotherapy and radiotherapy resistance, and glioblastomas are among the most hypoxic of solid tumours . Hypoxic cell clones do not actively divide due to lack of sufficient cellular energy and non‐dividing cells are more resistant to chemo‐radiotherapy as their DNA is more compacted and shielded with histone and non‐histone proteins.…”

Section: Rationale For Employing Methenamine To Treat and Chemo‐radiomentioning

confidence: 99%

“…In tumours, hypoxia aggravates chemotherapy and radiotherapy resistance, and glioblastomas are among the most hypoxic of solid tumours. 25 Hypoxic cell clones do not actively divide due to lack of sufficient cellular energy and non-dividing cells are more resistant to chemo-radiotherapy as their DNA is more compacted and shielded with histone and non-histone proteins. Moreover, hypoxia activates purinergic signalling allowing multi-drug resistance in glioblastoma.…”

Section: R Ationale For Employing Me Thenamine To Tre At and Chemo mentioning

confidence: 99%

Methenamine's journey of 160 years: Repurposal of an old urinary antiseptic for treatment and hypoxic radiosensitization of cancers and glioblastoma

Altinöz

Özpınar

Ozpinar

et al. 2019

Clin Exp Pharma Physio

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Summary Methenamine (hexamethylenetetramine, hexamine, urotropine) is a compound discovered in 1859, which is still currently being used as a urinary antiseptic. Methenamine is highly soluble in water and polar solvents, and its molecular constitution is similar to adamantane compounds with tetrahedral cage like structure. In acidic conditions, methenamine decomposes to formaldehyde and ammonia. Recently, methenamine has gained a renewal of interest due to antibiotic‐resistant bacteria urinary tract infections; interestingly, bacteria cannot gain resistance to formaldehyde. In 1968, David and Burkitt reported remarkable regression of four Burkitt Lymphoma patients in eight subjects who were treated with septicemine (a solution containing 6.3 g of methenamine iodomethylate and 1 g of methenamine sodium benzoate in 100 cc distilled water). Unfortunately, these striking observations did not gain interest in the medical community; despite experimental models that showed that methenamine synergized with hyperthermia, radiation, and chemotherapy to block cancer growth. As the hypoxic core of tumours have an acidic pH, it would be plausible to expect that methenamine would selectively target dormant, non‐proliferative, and treatment‐resistant cancer clones in large tumours. Moreover, previous data suggests that methenamine can be safely used intravenously and for treatment of infections of the central nervous system. It may therefore be an effective adjuvant in treatment of systemic cancers and glioblastoma.

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“…We have earlier shown the synergistic effect of 2-deoxy-D-glucose and cisplatin on cell monolayers under both hypoxia and normoxia. However this involved a distinct mechanism of conversion of autophagy to apoptosis, and also the effect on cancer stem cells was not demonstrated [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…NS-398 was taken as the prototype COX-2 inhibitor which was used in combination with the drugs (BCNU, Temozolomide (TMZ), Cisplatin (CP) and 2-Deoxy-D- glucose (2-DG)). While TMZ and BCNU are being used in glioma [ 40 – 42 ], CP and 2-DG have been tried earlier [ 6 , 43 – 46 ]. We observed synergism under both hypoxia and normoxia, only with the combination of NS-398 and BCNU.…”

Section: Introductionmentioning

confidence: 99%

A drug combination targeting hypoxia induced chemoresistance and stemness in glioma cells

et al. 2018

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Hypoxia is a characteristic of solid tumors especially Glioblastoma and is critical to chemoresistance. Cancer stem cells present in hypoxic niches are known to be a major cause of the progression, metastasis and relapse. We tried to identify synergistic combinations of drugs effective in both hypoxia and normoxia in tumor cells as well as in cancer stem cells. Since COX-2 is over-expressed in subset of glioblastoma and is also induced in hypoxia, we studied combinations of a prototype Cyclooxygenase (COX-2) inhibitor, NS-398 with various drugs (BCNU, Temozolomide, 2-Deoxy-D-glucose and Cisplatin) for their ability to abrogate chemoresistance under both severe hypoxia (0.2% O2) and normoxia (20% O2) in glioma cells. The only effective combination was of NS-398 and BCNU which showed a synergistic effect in both hypoxia and normoxia. This synergism was evident at sub-lethal doses for either of the single agent. The effectiveness of the combination resulted from increased pro- apoptotic and decreased anti-apoptotic molecules and increased caspase activity. PGE2 levels, a manifestation of COX-2 activity were increased during hypoxia, but were reduced by the combination during both hypoxia and normoxia. The combination reduced the levels of epithelial-mesenchymal transition (EMT) markers. It also resulted in a greater reduction of cell migration. While single drugs could reduce the number of gliomaspheres, the combination successfully abrogated their formation. The combination also resulted in a greater reduction of the cancer stem cell marker CD133. This combination could be a prototype of possible therapy in a tumor with a high degree of hypoxia like glioma.

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Synergistic increase in efficacy of a combination of 2-deoxy-d-glucose and cisplatin in normoxia and hypoxia: switch from autophagy to apoptosis

Cited by 24 publications

References 34 publications

Low dose of 2-deoxy-D-glucose kills acute lymphoblastic leukemia cells and reverses glucocorticoid resistance via N-linked glycosylation inhibition under normoxia

Low dose of 2-deoxy-D-glucose kills acute lymphoblastic leukemia cells and reverses glucocorticoid resistance via N-linked glycosylation inhibition under normoxia

Methenamine's journey of 160 years: Repurposal of an old urinary antiseptic for treatment and hypoxic radiosensitization of cancers and glioblastoma

A drug combination targeting hypoxia induced chemoresistance and stemness in glioma cells

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