Home LiteratureArticle Details
PMID: 26959881 Published · ppublish English Journal Article

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

Oncotarget ·Vol. 7 ·No. 14 ·2016-04-05 ·Pages 18965-77

Voltan R, Rimondi E, Melloni E, Gilli P, Bertolasi V, Casciano F, Rigolin GM, Zauli G, Secchiero P

Abstract

Metformin and the mitochondrial targeting dichloroacetate (DCA) have recently received attention due to their ability to inhibit anaerobic glycolysis, which renders most cancer cells resistant to apoptosis induction. We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in both B leukemic cell lines and primary B-chronic lymphocytic leukemia (B-CLL) patients' cells and its anti-leukemic activity was enhanced when used in combination with DCA. In order to overcome the problems of poor bioavailability and cellular uptake, which limit DCA efficacy, we have designed and synthetized cocrystals consisting of Metformin and DCA (Met-DCA) at different stoichiometric ratios. Of note, the MetH(2)(++)•2DCA(-) cocrystal exhibited enhanced in vitro anti-leukemic activity, with respect to the treatment with the mix consisting of Metformin plus DCA. In particular, the treatment with the cocrystal MetH(2)(++)•2DCA(-) induced a synergistic apoptotic cell death coupled to a marked down-modulation of the anti-apoptotic Mcl-1 protein. Taken together, our data emphasize that innovative compounds based on Metformin-DCA combination merit to be further evaluated as chemotherapeutic agents for the treatment of B-CLL.

Keywords
B chronic leukemic cells Mcl-1 apoptosis metformin sodium dichloroacetate
MeSH Terms
Antineoplastic Combined Chemotherapy Protocols/pharmacology Apoptosis/drug effects Cell Death/drug effects Cell Line, Tumor Dichloroacetic Acid/administration & dosage,pharmacology Humans Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy,genetics,metabolism,pathology Metformin/administration & dosage,pharmacology Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors,genetics,metabolism
Chemicals
MCL1 protein, human Myeloid Cell Leukemia Sequence 1 Protein Metformin Dichloroacetic Acid
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Voltan Rebecca
Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
Rimondi Erika
Department of Life Sciences, University of Trieste, Trieste, Italy.
Melloni Elisabetta
Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
Gilli Paola
Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
Bertolasi Valerio
Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
Casciano Fabio
Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
Rigolin Gian Matteo
Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy.
Zauli Giorgio
Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
Secchiero Paola
Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
References (61)
61 references, click to expand
  1. Metformin, an old drug, brings a new era to cancer therapy.
    Cancer J. 2015 Mar-Apr;21(2):70-4 PMID: 25815846
  2. Role of the extracellular domain of human herpesvirus 7 glycoprotein B in virus binding to cell surface heparan sulfate proteoglycans.
    J Virol. 1997 Jun;71(6):4571-80 PMID: 9151851
  3. Delving deeper: MCL-1's contributions to normal and cancer biology.
    Trends Cell Biol. 2013 Jan;23(1):22-9 PMID: 23026029
  4. Targeting cancer cell metabolism in pancreatic adenocarcinoma.
    Oncotarget. 2015 Jul 10;6(19):16832-47 PMID: 26164081
  5. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up.
    Blood. 2008 Oct 15;112(8):3322-9 PMID: 18689542
  6. TP53 mutation and survival in chronic lymphocytic leukemia.
    J Clin Oncol. 2010 Oct 10;28(29):4473-9 PMID: 20697090
  7. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.
    Biochem J. 2000 Jun 15;348 Pt 3:607-14 PMID: 10839993
  8. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth.
    Cancer Cell. 2007 Jan;11(1):37-51 PMID: 17222789
  9. First MCL-1-selective BH3 mimetics as potential therapeutics for targeted treatment of cancer.
    Cell Death Dis. 2015 Jul 09;6:e1810 PMID: 26158516
  10. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer.
    Br J Cancer. 2008 Oct 7;99(7):989-94 PMID: 18766181
  11. Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect.
    PLoS One. 2009 Sep 15;4(9):e7033 PMID: 19753307
  12. Autophagy and protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha kinase (eIF2α) pathway protect ovarian cancer cells from metformin-induced apoptosis.
    Mol Carcinog. 2016 Apr;55(4):346-56 PMID: 25663310
  13. Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells.
    Cancer Lett. 2014 May 1;346(2):300-8 PMID: 24480191
  14. Human immunodeficiency virus type 1 envelope glycoprotein gp120-mediated killing of human haematopoietic progenitors (CD34+ cells).
    J Gen Virol. 1992 Feb;73 ( Pt 2):417-21 PMID: 1371543
  15. Akt-dependent glucose metabolism promotes Mcl-1 synthesis to maintain cell survival and resistance to Bcl-2 inhibition.
    Cancer Res. 2011 Aug 1;71(15):5204-13 PMID: 21670080
  16. Pharmaceutical Cocrystals and Their Physicochemical Properties.
    Cryst Growth Des. 2009 Jun 3;9(6):2950-2967 PMID: 19503732
  17. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies.
    Cell Death Dis. 2015 Jan 15;6:e1593 PMID: 25590803
  18. A phase I open-labeled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors.
    Invest New Drugs. 2015 Jun;33(3):603-10 PMID: 25762000
  19. 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 Oct;12 (10 ):2145-56 PMID: 23883584
  20. Inactivation of TP53 correlates with disease progression and low miR-34a expression in previously treated chronic lymphocytic leukemia patients.
    Blood. 2013 May 2;121(18):3650-7 PMID: 23525797
  21. Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL.
    Oncotarget. 2015 Jun 30;6(18):16559-72 PMID: 26041884
  22. miR-34a induces the downregulation of both E2F1 and B-Myb oncogenes in leukemic cells.
    Clin Cancer Res. 2011 May 1;17 (9):2712-24 PMID: 21367750
  23. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.
    Adv Enzyme Regul. 1984;22:27-55 PMID: 6382953
  24. Low MCL-1 mRNA expression correlates with prolonged survival in B-cell chronic lymphocytic leukemia.
    Leukemia. 2008 Jun;22(6):1291-3 PMID: 18046444
  25. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  26. Metformin displays anti-myeloma activity and synergistic effect with dexamethasone in in vitro and in vivo xenograft models.
    Cancer Lett. 2015 Jan 28;356(2 Pt B):443-53 PMID: 25305450
  27. 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 Apr 30;113(18):4300-8 PMID: 19190243
  28. Targeting BCL2 for the treatment of lymphoid malignancies.
    Semin Hematol. 2014 Jul;51(3):219-27 PMID: 25048785
  29. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells.
    Oncotarget. 2015 Sep 8;6(26):22624-40 PMID: 26265439
  30. VEGF receptors on chronic lymphocytic leukemia (CLL) B cells interact with STAT 1 and 3: implication for apoptosis resistance.
    Leukemia. 2005 Apr;19(4):513-23 PMID: 15703780
  31. 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 Jan;23(1):117-24 PMID: 18843282
  32. Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts.
    PLoS One. 2013 Aug 23;8(8):e74420 PMID: 24009772
  33. Monoallelic and biallelic inactivation of TP53 gene in chronic lymphocytic leukemia: selection, impact on survival, and response to DNA damage.
    Blood. 2009 Dec 17;114(26):5307-14 PMID: 19850740
  34. Role of AMP-activated protein kinase in mechanism of metformin action.
    J Clin Invest. 2001 Oct;108(8):1167-74 PMID: 11602624
  35. Cancer's molecular sweet tooth and the Warburg effect.
    Cancer Res. 2006 Sep 15;66(18):8927-30 PMID: 16982728
  36. Targeting AMPK for cancer prevention and treatment.
    Oncotarget. 2015 Apr 10;6(10):7365-78 PMID: 25812084
  37. 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 Aug 28;6(25):21208-24 PMID: 26056043
  38. 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 Jan 15;111(2):846-55 PMID: 17928528
  39. Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib.
    Br J Cancer. 2013 Apr 30;108(8):1624-33 PMID: 23531700
  40. HIV type 1 extracellular Tat protein stimulates growth and protects cells of BK virus/tat transgenic mice from apoptosis.
    AIDS Res Hum Retroviruses. 1995 Sep;11(9):1039-48 PMID: 8554901
  41. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers.
    Blood. 2008 Nov 1;112(9):3807-17 PMID: 18599795
  42. 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 Feb 15;17 (4):762-70 PMID: 21106726
  43. BH3 mimetics: status of the field and new developments.
    Mol Cancer Ther. 2013 Sep;12 (9):1691-700 PMID: 23974697
  44. STAT3 is constitutively phosphorylated on serine 727 residues, binds DNA, and activates transcription in CLL cells.
    Blood. 2010 Apr 8;115(14):2852-63 PMID: 20154216
  45. Sodium dichloroacetate exhibits anti-leukemic activity in B-chronic lymphocytic leukemia (B-CLL) and synergizes with the p53 activator Nutlin-3.
    Oncotarget. 2014 Jun 30;5(12 ):4347-60 PMID: 24962518
  46. Changes of nuclear protein kinase C activity and isotype composition in PC12 cell proliferation and differentiation.
    Exp Cell Res. 1996 Apr 10;224(1):72-8 PMID: 8612693
  47. STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells.
    Biochem J. 2005 Dec 1;392(Pt 2):335-44 PMID: 16048438
  48. Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells.
    Leukemia. 2013 Nov;27(11):2129-38 PMID: 23568147
  49. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling.
    Cell Death Dis. 2014 Feb 27;5:e1088 PMID: 24577086
  50. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines?
    Chem Commun (Camb). 2004 Sep 7;(17):1889-96 PMID: 15340589
  51. In vitro exposure to human immunodeficiency virus type 1 induces apoptotic cell death of the factor-dependent TF-1 hematopoietic cell line.
    Blood. 1994 Jan 1;83(1):167-75 PMID: 7506078
  52. Combination of sulindac and dichloroacetate kills cancer cells via oxidative damage.
    PLoS One. 2012;7(7):e39949 PMID: 22866174
  53. Metformin in cancer treatment and prevention.
    Annu Rev Med. 2015;66:17-29 PMID: 25386929
  54. Metabolic modulation of glioblastoma with dichloroacetate.
    Sci Transl Med. 2010 May 12;2(31):31ra34 PMID: 20463368
  55. Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation.
    Oncogene. 2010 Mar 18;29(11):1641-52 PMID: 19966861
  56. Resistance to Dasatinib in primary chronic lymphocytic leukemia lymphocytes involves AMPK-mediated energetic re-programming.
    Oncotarget. 2013 Dec;4(12):2550-66 PMID: 24334291
  57. Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin.
    Clin Cancer Res. 2015 Mar 1;21(5):1161-71 PMID: 25542900
  58. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness.
    Clin Cancer Res. 2009 Feb 1;15(3):995-1004 PMID: 19188171
  59. The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway.
    Oncotarget. 2015 Feb 10;6(4):2385-96 PMID: 25544776
  60. Evidence for a human immunodeficiency virus type 1-mediated suppression of uninfected hematopoietic (CD34+) cells in AIDS patients.
    J Infect Dis. 1992 Oct;166(4):710-6 PMID: 1382106
  61. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo.
    Breast Cancer Res Treat. 2010 Feb;120(1):253-60 PMID: 19543830
Article Info
Journal
Oncotarget
Abbr.
Oncotarget
ISSN
1949-2553
DOI
10.18632/oncotarget.7879
Published
2016-04-05
Pages
18965-77
Language
English
Region
United States
NLM ID
101532965
PMCID
PMC4951344
Subset
IM
External Links
PubMed source DOI: 10.18632/oncotarget.7879 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2