Metformin combined with sodium dichloroacetate promotes B leukemic cell death by suppressing anti-apoptotic protein Mcl-1

Oncotarget

Volumn 7, Issue 14, 2016, Pages 18965-18977

  Voltan, Rebecca ^a   Rimondi, Erika ^b   Melloni, Elisabetta ^a   Gilli, Paola ^a   Bertolasi, Valerio ^a   Casciano, Fabio ^a   Rigolin, Gian Matteo ^a   Zauli, Giorgio ^a   Secchiero, Paola ^a  

^a UNIVERSITY OF FERRARA   (Italy)

^b UNIVERSITY OF TRIESTE   (Italy)

Author keywords

Apoptosis; B chronic leukemic cells; Mcl 1; Metformin; Sodium dichloroacetate

Indexed keywords

ANTILEUKEMIC AGENT; DICHLOROACETIC ACID PLUS METFORMIN; METFORMIN; PROTEIN MCL 1; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; DICHLOROACETIC ACID; MCL1 PROTEIN, HUMAN;

ANTINEOPLASTIC ACTIVITY; ARTICLE; B CELL LEUKEMIA; B CHRONIC LYMPHOCYTIC LEUKEMIA; B-CELL LEUKEMIA CELL LINE; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CHRONIC LYMPHATIC LEUKEMIA; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG CYTOTOXICITY; DRUG POTENTIATION; HUMAN; HUMAN CELL; IN VITRO STUDY; MONOTHERAPY; STOICHIOMETRY; ANTAGONISTS AND INHIBITORS; APOPTOSIS; CELL DEATH; DRUG EFFECTS; GENETICS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; METABOLISM; PATHOLOGY; TUMOR CELL LINE;

ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; APOPTOSIS; CELL DEATH; CELL LINE, TUMOR; DICHLOROACETIC ACID; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; METFORMIN; MYELOID CELL LEUKEMIA SEQUENCE 1 PROTEIN;

EID: 84975483805     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.7879     Document Type: Article

References (64)

1. Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer. 2008; 99: 989-994.
2. Kim JW, Dang CV. Cancer's molecular sweet tooth and the Warburg effect. Cancer Res. 2006; 66: 8927-8930.
3. Chen Y, Cairns R, Papandreou I, Koong A, Denko NC. Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect. PLoS One. 2009; 4: e7033.
4. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007; 11: 37-51.
5. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010; 2: 31ra34.
6. Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat. 2010; 120: 253-260.
7. Ayyanathan K, Kesaraju S, Dawson-Scully K, Weissbach H. Combination of sulindac and dichloroacetate kills cancer cells via oxidative damage. PLoS One. 2012; 7: e39949.
8. Sanchez WY, McGee SL, Connor T, Mottram B, Wilkinson A, Whitehead JP, Vuckovic S, Catley L. Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib. Br J Cancer. 2013; 108: 1624-1633.
9. Agnoletto C, Melloni E, Casciano F, Rigolin GM, Rimondi E, Celeghini C, Brunelli L, Cuneo A, Secchiero P, Zauli G. Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3. Oncotarget. 2014; 5: 4347-4360 doi: 10.18632/oncotarget.2018
10. Agnoletto C, Brunelli L, Melloni E, Pastorelli R, Casciano F, Rimondi E, Rigolin GM, Cuneo A, Secchiero P, Zauli G. The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway. Oncotarget. 2015; 6: 2385-2396. doi: 10.18632/oncotarget.2960
11. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000; 348: 607-614.
12. Scotland S, Saland E, Skuli N, de Toni F, Boutzen H, Micklow E, Sénégas I, Peyraud R, Peyriga L, Théodoro F, Dumon E, Martineau Y, Danet-Desnoyers G, Bono F, Rocher C, Levade T, Manenti S, Junot C, Portais JC, Alet N, Récher C, Selak MA, Carroll M, Sarry JE. Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells. Leukemia. 2013; 27: 2129-2138.
13. Leclerc GM, Leclerc GJ, Kuznetsov JN, DeSalvo J, Barredo JC. Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts. PLoS One. 2013; 8: e74420.
14. Martinez Marignac VL, Smith S, Toban N, Bazile M, Aloyz R. Resistance to Dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic re-programming. Oncotarget. 2013; 4: 2550-2566. doi: 10.18632/oncotarget.1508
15. Cohen R, Neuzillet C, Tijeras-Raballand A, Faivre S, de Gramont A, Raymond E. Targeting cancer cell metabolism in pancreatic adenocarcinoma. Oncotarget. 2015; 6: 16832-16847 doi: 10.18632/oncotarget.4160
16. Morales DR, Morris AD. Metformin in cancer treatment and prevention. Annu Rev Med. 2015; 66: 17-29.
17. He H, Ke R, Lin H, Ying Y, Liu D, Luo Z. Metformin, an old drug, brings a new era to cancer therapy. Cancer J. 2015; 21: 70-74.
18. Li W, Saud SM, Young MR, Chen G, Hua B. Targeting AMPK for cancer prevention and treatment. Oncotarget. 2015; 6: 7365-7378. doi: 10.18632/oncotarget.3629
19. Choi YW, Lim IK. Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells. Cancer Lett. 2014; 346: 300-308.
20. Zenz T, Kröber A, Scherer K, Häbe S, Bühler A, Benner A, Denzel T, Winkler D, Edelmann J, Schwänen C, Döhner H, Stilgenbauer S. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with longterm follow-up. Blood. 2008; 112: 3322-3329.
21. Dicker F, Herholz H, Schnittger S, Nakao A, Patten N, Wu L, Kern W, Haferlach T, Haferlach C. The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype. Leukemia. 2009; 23: 117-124.
22. Rossi D, Cerri M, Deambrogi C, Sozzi E, Cresta S, Rasi S, De Paoli L, Spina V, Gattei V, Capello D, Forconi F, Lauria F, Gaidano G. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness. Clin Cancer Res. 2009; 15: 995-1004.
23. Malcikova J, Smardova J, Rocnova L, Tichy B, Kuglik P, Vranova V, Cejkova S, Svitakova M, Skuhrova Francova H, Brychtova Y, Doubek M, Brejcha M, Klabusay M et al. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage. Blood. 2009; 114: 5307-5314.
24. Zenz T, Eichhorst B, Busch R, Denzel T, Häbe S, Winkler D, Bühler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Döhner H et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010; 28: 4473-4479.
25. Dufour A, Palermo G, Zellmeier E, Mellert G, Duchateau-Nguyen G, Schneider S, Benthaus T, Kakadia PM, Spiekermann K, Hiddemann W, Braess J, Truong S, Patten N et al. Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients. Blood. 2013; 121: 3650-3657.
26. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22: 27-55.
27. Moon HS, Kim B, Gwak H, Suh DH, Song YS. Autophagy and protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha kinase (eIF2a) pathway protect ovarian cancer cells from metformininduced apoptosis. Mol Carcinog. 2016; 55:346-56. doi: 10.1002/mc.22284.
28. Yue W, Zheng X, Lin Y, Yang CS, Xu Q, Carpizo D, Huang H, DiPaola RS, Tan XL. Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2. Oncotarget. 2015; 6: 21208-21224. doi: 10.18632/oncotarget.4126
29. Zi FM, He JS, Li Y, Wu C, Yang L, Yang Y, Wang LJ, He DH, Zhao Y, Wu WJ, Zheng GF, Han XY, Huang H, Yi Q, Cai Z. Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models. Cancer Lett. 2015; 356: 443-453.
30. Dalva-Aydemir S, Bajpai R, Martinez M, Adekola KU, Kandela I, Wei C, Singhal S, Koblinski JE, Raje NS, Rosen ST, Shanmugam M. Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin. Clin Cancer Res. 2015; 21: 1161-1171.
31. Pepper C, Lin TT, Pratt G, Hewamana S, Brennan P, Hiller L, Hills R, Ward R, Starczynski J, Austen B, Hooper L, Stankovic T, Fegan C. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood. 2008; 112: 3807-3817.
32. Veronese L, Tournilhac O, Verrelle P, Davi F, Dighiero G, Chautard E, Veyrat-Masson R, Kwiatkowski F, Goumy C, Vago P, Travade P, Tchirkov A. Low MCL-1 mRNA expression correlates with prolonged survival in B-cell chronic lymphocytic leukemia. Leukemia. 2008; 22: 1291-1293.
33. Coloff JL, Macintyre AN, Nichols AG, Liu T, Gallo CA, Plas DR, Rathmell JC. Akt dependent glucose metabolism promotes Mcl-1synthesis to maintain cell survival and resistance to Bcl-2 inhibition. Cancer Res. 2011; 71: 5204-5213.
34. Feng Y, Ke C, Tang Q, Dong H, Zheng X, Lin W, Ke J, Huang J, Yeung SC, Zhang H. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell death & disease. 2014; 5: e1088.
35. Bhattacharya S, Ray RM, Johnson LR. STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells. The Biochemical journal. 2005; 392: 335-344.
36. Hazan-Halevy I, Harris D, Liu Z, Liu J, Li P, Chen X, Shanker S, Ferrajoli A, Keating MJ, Estrov Z. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells. Blood. 2010; 115: 2852-2863.
37. Longo PG, Laurenti L, Gobessi S, Sica S, Leone G, Efremov DG. The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells. Blood. 2008; 111: 846-855.
38. Lee YK, Shanafelt TD, Bone ND, Strege AK, Jelinek DF, Kay NE. VEGF receptors on chronic lymphocytic leukemia (CLL) B cells interact with STAT 1 and 3: implication for apoptosis resistance. Leukemia. 2005; 19: 513-523.
39. Bruno S, Ledda B, Tenca C, Ravera S, Orengo AM, Mazzarello N, Pesenti E, Casciaro S, Racchi O, Ghiotto F, Marini C, Sambuceti G, DeCensi A, Fais F. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells. Oncotarget. 2015; 6: 22624-22640. doi: 10.18632/oncotarget.4168
40. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108: 1167-1174.
41. Kim SM, Yun MR, Hong YK, Solca F, Kim JH, Kim HJ, Cho BC. Glycolysis inhibition sensitizes non-small cell lung cancer with T790M mutation to irreversible EGFR inhibitors via translational suppression of Mcl-1 by AMPK activation. Mol Cancer Ther. 2013; 12: 2145-2156.
42. Pradelli LA, Bénéteau M, Chauvin C, Jacquin MA, Marchetti S, Muñoz-Pinedo C, Auberger P, Pende M, Ricci JE. Glycolysis inhibition sensitizes tumor cells to death receptorsinduced apoptosis by AMP kinase activation leading to Mcl-1 block in translation. Oncogene. 2010; 29: 1641-1652.
43. Center for Drug Evaluation and Research. Guidance for industry: regulatory classification of pharmaceutical co-crystals. Rockville, Maryland: United States Food and Drug Administration. 2011.
44. Schultheiss N, Newman A. Pharmaceutical Cocrystals and Their Physicochemical Properties. Cryst Growth Des. 2009; 9: 2950-2967.
45. Almarsson O, Zaworotko MJ. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines? Chem Commun (Camb). 2004; 17: 1889-1896.
46. Chu QS, Sangha R, Spratlin J, J Vos L, Mackey JR, McEwan AJ, Venner P, Michelakis ED. A phase I open-labeled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors. Invest New Drugs. 2015; 33: 603-610.
47. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646-674.
48. Billard C. BH3 mimetics: status of the field and new developments. Molecular cancer therapeutics. 2013; 12: 1691-1700.
49. Anderson MA, Huang D, Roberts A. Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol. 2014; 51: 219-227.
50. Perciavalle RM, Opferman JT. Delving deeper: MCL-1's contributions to normal and cancer biology. Trends Cell Biol. 2013; 23: 22-29.
51. De Falco F, Sabatini R, Del Papa B, Falzetti F, Di Ianni M, Sportoletti P, Baldoni S, Screpanti I, Marconi P, Rosati E. Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL. Oncotarget. 2015; 6: 16559-16572. doi: 10.18632/oncotarget.4116
52. Besbes S, Billard C. First MCL-1-selective BH3 mimetics as potential therapeutics for targeted treatment of cancer. Cell Death Dis. 2015; 6: e1810.
53. Choudhary GS, Al-Harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, Hsi ED, Almasan A. MCL-1 and BCL-xLdependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015; 6: e1593.
54. Secchiero P, Melloni E, di Iasio MG, Tiribelli M, Rimondi E, Corallini F, Gattei V, Zauli G. Nutlin-3 up-regulates the expression of Notch1 in both myeloid and lymphoid leukemic cells, as part of a negative feedback antiapoptotic mechanism. Blood. 2009; 113: 4300-4308.
55. Zauli G, Voltan R, di Iasio MG, Bosco R, Melloni E, Sana ME, Secchiero P. miR-34a induces the down-regulation of both E2F1 and B-Myb oncogenes in leukemic cells. Clin Cancer Res. 2011; 17: 2712-2724.
56. Zauli G, Re MC, Visani G, Furlini G, Mazza P, Vignoli M, La Placa M. Evidence for a human immunodeficiency virus type 1-mediated suppression of uninfected hematopoietic (CD34+) cells in AIDS patients. J Infect Dis. 1992; 166: 710-716.
57. Zauli G, Re MC, Furlini G, Giovannini M, La Placa M. Human immunodeficiency virus type 1 envelope glycoprotein gp120-mediated killing of human haematopoietic progenitors (CD34+ cells). J Gen Virol. 1992; 73: 417-421.
58. Campioni D, Corallini A, Zauli G, Possati L, Altavilla G, Barbanti-Brodano G. HIV type 1 extracellular tat protein stimulates growth and protects cells of BK virus/tat transgenic mice from apoptosis. AIDS Res Hum Retroviruses. 1995; 11: 1039-1048.
59. Zauli G, Voltan R, Bosco R, Melloni E, Marmiroli S, Rigolin GM, Cuneo A, Secchiero P. Dasatinib plus Nutlin-3 shows synergistic antileukemic activity in both p53 wild-type and p53 mutated B chronic lymphocytic leukemias by inhibiting the Akt pathway. Clin Cancer Res. 2011; 17: 762-770.
60. Borgatti P, Mazzoni M, Carini C, Neri LM, Marchisio M, Bertolaso L, Previati M, Zauli G, Capitani S. Changes of nuclear protein kinase C activity and isotype composition in PC12 cell proliferation and differentiation. Exp Cell Res. 1996; 224: 72-78.
61. Macrae CF, Bruno IJ, Chisholm JA, Edgington PR, McCabe P, Pidcock E, Rodriguez-Monge L, Taylor R, van de Streek J, Wood PA. Mercury CSD2.0-new features for the visualization and investigation of crystal structures. J Appl Crystallogr. 2008; 41: 466-470.
62. Pérez-Fernández R, Fresno N, Goya P, Elguero J, Menéndez-Taboada L, García-Granda S, Marco C. Structure and thermodynamical properties of metformin salicylate. Cryst Growth Des. 2013; 13: 1780-1785.
63. Zauli G, Vitale M, Re MC, Furlini G, Zamai L, Falcieri E, Gibellini D, Visani G, Davis BR, Capitani S, La Placa M. In vitro exposure to human immunodeficiency virus type-1 induces apoptotic cell death of the factordependent TF-1 hematopoietic cell line. Blood. 1994; 83: 167-175.
64. Secchiero P, Sun D, De Vico AL, Crowley RW, Reitz MS, Zauli G, Lusso P, Gallo RC. Role of the extracellular domain of human herpesvirus 7 glycoprotein B in virus binding to cell surface heparan sulfate proteoglycans. J Virol. 1997; 71: 4571-4580.