Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death

Catanzaro, Daniela; Gaude, Edoardo; Orso, Genny; Giordano, Carla; Guzzo, Giulia; Rasola, Andrea; Ragazzi, Eugenio; Caparrotta, Laura; Frezza, Christian; Montopoli, Monica

doi:10.18632/oncotarget.4945

Cited by 107 publications

(115 citation statements)

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“…Several agents are known to sensitize cancer cells to cisplatin, one of which is 6-AN (49). This effect is primarily due to the action of 6-amino-NAD(P+), which results in intracellular cisplatin enrichment and the accumulation of plasma tumor DNA adducts (50). Pretreatment with 6-AN has been demonstrated to sensitize different tumor cells to cisplatin cytotoxicity, even cisplatin-resistant cells; this may explain the synergistic effects of 6-AN and cisplatin on bladder cancer cells (49,50).…”

Section: Discussionmentioning

confidence: 99%

“…This effect is primarily due to the action of 6-amino-NAD(P+), which results in intracellular cisplatin enrichment and the accumulation of plasma tumor DNA adducts (50). Pretreatment with 6-AN has been demonstrated to sensitize different tumor cells to cisplatin cytotoxicity, even cisplatin-resistant cells; this may explain the synergistic effects of 6-AN and cisplatin on bladder cancer cells (49,50). However, it has also been reported that 6-AN may cause neurotoxicity or hematological toxicity under certain conditions (43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

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Modulation of G6PD affects bladder cancer via ROS accumulation and the AKT pathway in vitro

Chen

Zhu

et al. 2018

Int J Oncol

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Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme of the pentose phosphate pathway. Multiple studies have previously revealed that elevated G6PD levels promote cancer progression in numerous tumor types; however, the underlying mechanism remains unclear. In the present study, it was demonstrated that high G6PD expression is a poor prognostic factor in bladder cancer, and the levels of G6PD expression increase with increasing tumor stage. Patients with bladder cancer with high G6PD expression had worse survival rates compared with those with lower G6PD expression in resected tumors. In vitro experiments revealed that knockdown of G6PD suppressed cell viability and growth in Cell Counting Kit-8 and colony formation assays, and increased apoptosis in bladder cancer cell lines compared with normal cells. Further experiments indicated that the weakening of the survival ability in G6PD-knockdown bladder cancer cells may be explained by intracellular reactive oxygen species accumulation and protein kinase B pathway suppression. Furthermore, it was additionally revealed that 6-aminonicotinamide (6-AN), a competitive G6PD inhibitor, may be a potential therapy for bladder cancer, particularly in cases with high G6PD expression, and that the combination of cisplatin and 6-AN may optimize the clinical dose or minimize the side effects of cisplatin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Modulation of G6PD affects bladder cancer via ROS accumulation and the AKT pathway in vitro

Chen

Zhu

et al. 2018

Int J Oncol

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“…Oxidative stress has been shown to sensitive tumor cells to chemotherapeutics41. One study showed that inhibition of G6PDH, the committed step of the pentose phosphate pathway that is regulated by the NADPH/NADP ratio, sensitizes cisplatin-resistant cancer cells42. Previous work has shown that the PKM2 isozyme implicated in inducing the Warburg metabolic phenotype also responds to reactive oxygen species by increasing oxidative stress resistance through increasing pentose phosphate pathway flux43.…”

Section: Discussionmentioning

confidence: 99%

Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism

Zielinski

Jamshidi

Corbett

et al. 2017

Sci Rep

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Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood.

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“…For ex am ple, in ovar ian can cer, one of the most lethal can cers world wide, cis platin re sis tant cells dis played in creased OX PHOS and ROS lev els com pared to sen si tive cells, and this phe no type was re versed upon phar ma co log i cal in hi bi tion of mi to chon dr ial OX PHOS or ROS scav eng ing [133]. The op po site phe nom e non, chemore sis tance by a low ox ida tive me tab o lism, has been iden ti fied as well [134,135]. De spite that these two types of meta bolic chemore sis tance may ap pear to be op po site, they both act through a de creased ca pa bil ity of mi to chon dria to gen er ate ROS, ei ther by up reg u lat ing an tiox i dant de fenses in a high OX PHOS con text [136] or by de creas ing ROS gen er a tion at the elec tron trans port chain when OX PHOS is low.…”

Section: Metabolic Regulation Of Cancer Cell Deathmentioning

confidence: 97%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

177

139

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Available online xxx Keywords:Can cer Me tab o lism Mi to chon dria Het ero gene ity Metas ta sis A B S T R A C T Al tered me tab o lism in can cer cells is piv otal for tu mor growth, most no tably by pro vid ing en ergy, re duc ing equiv a lents and build ing blocks while sev eral metabo lites ex ert a sig nal ing func tion pro mot ing tu mor growth and pro gres sion. A can cer tis sue can not be sim ply re duced to a bulk of pro lif er at ing cells. Tu mors are in deed com plex and dy namic struc tures where sin gle cells can het ero ge neously per form var i ous bi o log i cal ac tiv i ties with dif fer ent meta bolic re quire ments. Be cause tu mors are com posed of dif fer ent types of cells with meta bolic ac tiv i ties af fected by dif fer ent spa tial and tem po ral con texts, it is im por tant to ad dress me tab o lism tak ing into ac count cel lu lar and bi o log i cal het ero gene ity. In this re view, we de scribe this het ero gene ity also in meta bolic fluxes, thus show ing the rel a tive con tri bu tion of dif fer ent meta bolic ac tiv i ties to tu mor pro gres sion ac cord ing to the cel lu lar con text. This ar ti cle is part of a Spe cial Is sue en ti tled Res pi ra tory com plex I, edited by Giuseppe Gas parre, Ro drigue Rossig nol and Pierre Son veaux. Abbreviations: ACL, ATP cit rate lyase; AMPK, adeno sine monophos phate ki nase; ARG1, L argi nine me tab o liz ing en zyme arginase 1; BCAA, branched chain amino acid; Bcl2, B cell lym phoma 2; CAF, can cer as so ci ated fi brob last; CIC, can cer ini ti at ing cell; COX2, cy tochrome ox i dase; CSC, can cer stem cell; CREB, cyclic adeno sine monophos phate re sponse el e ment bind ing pro tein; DEC1, dif fer en tially ex pressed in chon dro cytes 1; EMT, ep ithe lial to mes enchy mal tran si tion; FAK, fo cal ad he sion ki nase; FAS, fatty acid syn thase; FBP, fruc tose 1,6 bis pho s phate; FDG PET, [ F] flu o rodeoxyglu cose positron emis sion to mog ra phy; GAPDH, glyc er alde hyde 3 phos phate de hy dro ge nase; HIF 1, hy poxia ac ti vated fac tor 1; HK2, hex ok i nase 2; HMGB1, high mo bil ity group box 1; HU VEC, hu man um bil i cal vein en dothe lial cell; IFN γ, in ter feron gamma; LDH, lac tate de hy dro ge nase; MEF, murine em bry onic fi brob last; MET, mes enchy mal to ep ithe lial tran si tion; MRI, mag netic res o nance imag ing; mTORC1, mam malian tar get of ra pamycin com plex 1; NSCLC, non small cell lung can cer; OX PHOS, ox ida tive phos pho ry la tion; PDAC, pan cre atic duc tal ade no car ci noma; PHD, pro lyl hy drox y lase; pHe, ex tra cel lu lar pH; pHi, in tra cel lu lar pH; PK, pyru vate ki nase; PPP, pen tose phos phate path way; REDD1, reg u lated in de vel op ment and DNA dam age re sponse 1; RhoA, Ras ho molog gene fam ily, mem ber A; ROS, re ac tive oxy gen species; SASP, senes cence as so ci ated se cre tory phe no type; SCO2, syn the sis of cy tochrome ox i dase 2; SGK 1, serum and glu co cor ti coid reg u lated ki nase 1 Sirt1, sir tuin 1; TAM, tu mor as so ci ated macrophage; TIGAR, TP53 in duced gly col y ...

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Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death

Cited by 107 publications

References 47 publications

Modulation of G6PD affects bladder cancer via ROS accumulation and the AKT pathway in vitro

Modulation of G6PD affects bladder cancer via ROS accumulation and the AKT pathway in vitro

Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism

Cancer metabolism in space and time: Beyond the Warburg effect

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