Deferasirox, an Oral Iron Chelator, with Gemcitabine Synergistically Inhibits Pancreatic Cancer Cell Growth and

Overview

Journal Oncotarget

Specialty Oncology

Date 2018 Jul 10

PMID 29983871

Citations 15

Authors

Shuhei Shinoda

Seiji Kaino

Shogo Amano

Hirofumi Harima

Toshihiko Matsumoto

Koichi Fujisawa

Taro Takami

Naoki Yamamoto

Takahiro Yamasaki

Isao Sakaida

Affiliations

Soon will be listed here.

Abstract

Objectives: Iron is an essential element for cell proliferation and growth processes. We have reported that deferasirox (DFX), an oral iron chelator, showed antiproliferative activity against pancreatic cancer cells. This study aimed to elucidate the effects of combination of gemcitabine (GEM), standard chemotherapy for pancreatic cancer, and DFX and .

Results: GEM+DFX showed antiproliferative activity and induced apoptosis in pancreatic cancer cells . GEM+DFX suppressed xenograft tumor growth and induced apoptosis without any serious side effects compared with control, GEM, and DFX (average tumor volume: control 697 mm vs GEM 372 mm, < 0.05; GEM 372 mm vs GEM+DFX 234 mm, < 0.05). RRM1 and RRM2 protein levels were substantially reduced by DFX in BxPC-3 .

Conclusion: GEM+DFX has significant anticancer effects on pancreatic cancer cell through RR activity suppression.

Methods: BxPC-3, a human pancreatic cancer cell line, was used in all experiments. Cellular proliferation rate was measured using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay. Apoptosis was evaluated by flow cytometry and by measuring caspase 3/7 activity with luminescence assay. In the tumor xenografts in nude mice models, when five weeks after engraftment, drug administration began (day 0). After treatment for 21 days, the mice were sacrificed and the tumors were excised. Apoptotic cells in xenografts were evaluated by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay. Protein levels of ribonucleotide reductase (RR) subunit 1 (RRM1) and RR subunit 2 (RRM2) in BxPC-3 cells were assessed by western blot .

Citing Articles

Crosstalk between FTH1 and PYCR1 dysregulates proline metabolism and mediates cell growth in KRAS-mutant pancreatic cancer cells.

Park J, Su Y, Fan C, Chen H, Qiu Y, Chen L Exp Mol Med. 2024; 56(9):2065-2081.

PMID: 39294443 PMC: 11447051. DOI: 10.1038/s12276-024-01300-4.

Iron chelators: as therapeutic agents in diseases.

Salimi Z, Afsharinasab M, Rostami M, Eshaghi Milasi Y, Mousavi Ezmareh S, Sakhaei F Ann Med Surg (Lond). 2024; 86(5):2759-2776.

PMID: 38694398 PMC: 11060230. DOI: 10.1097/MS9.0000000000001717.

Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy.

Fujisawa K, Matsumoto T, Yamamoto N, Yamasaki T, Takami T Metabolites. 2023; 13(10).

PMID: 37887398 PMC: 10609263. DOI: 10.3390/metabo13101073.

Repurposed Drugs in Gastric Cancer.

Araujo D, Ribeiro E, Amorim I, Vale N Molecules. 2023; 28(1).

PMID: 36615513 PMC: 9822219. DOI: 10.3390/molecules28010319.

An iron chelation-based combinatorial anticancer therapy comprising deferoxamine and a lactate excretion inhibitor inhibits the proliferation of cancer cells.

Fujisawa K, Takami T, Matsumoto T, Yamamoto N, Yamasaki T, Sakaida I Cancer Metab. 2022; 10(1):8.

PMID: 35550011 PMC: 9103045. DOI: 10.1186/s40170-022-00284-x.

References

Minami K, Shinsato Y, Yamamoto M, Takahashi H, Zhang S, Nishizawa Y . Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors. J Pharmacol Sci. 2015; 127(3):319-25. DOI: 10.1016/j.jphs.2015.01.006. View

Ceppi P, Volante M, Novello S, Rapa I, Danenberg K, Danenberg P . ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine. Ann Oncol. 2006; 17(12):1818-25. DOI: 10.1093/annonc/mdl300. View

Chabes A, Thelander L . Controlled protein degradation regulates ribonucleotide reductase activity in proliferating mammalian cells during the normal cell cycle and in response to DNA damage and replication blocks. J Biol Chem. 2000; 275(23):17747-53. DOI: 10.1074/jbc.M000799200. View

Saeki I, Yamamoto N, Yamasaki T, Takami T, Maeda M, Fujisawa K . Effects of an oral iron chelator, deferasirox, on advanced hepatocellular carcinoma. World J Gastroenterol. 2016; 22(40):8967-8977. PMC: 5083802. DOI: 10.3748/wjg.v22.i40.8967. View

Lui G, Obeidy P, Ford S, Tselepis C, Sharp D, Jansson P . The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action. Mol Pharmacol. 2012; 83(1):179-90. DOI: 10.1124/mol.112.081893. View

Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y . FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011; 364(19):1817-25. DOI: 10.1056/NEJMoa1011923. View

Kovacevic Z, Chikhani S, Lovejoy D, Richardson D . Novel thiosemicarbazone iron chelators induce up-regulation and phosphorylation of the metastasis suppressor N-myc down-stream regulated gene 1: a new strategy for the treatment of pancreatic cancer. Mol Pharmacol. 2011; 80(4):598-609. DOI: 10.1124/mol.111.073627. View

Yamamoto N, Yamasaki T, Takami T, Uchida K, Fujisawa K, Matsumoto T . Deferasirox, an oral iron chelator, prevents hepatocarcinogenesis and adverse effects of sorafenib. J Clin Biochem Nutr. 2016; 58(3):202-9. PMC: 4865599. DOI: 10.3164/jcbn.15-127. View

Suenaga S, Kuramitsu Y, Kaino S, Maehara S, Maehara Y, Sakaida I . Active hexose-correlated compound down-regulates HSP27 of pancreatic cancer cells, and helps the cytotoxic effect of gemcitabine. Anticancer Res. 2014; 34(1):141-6. View

10.

Torti S, Torti F . Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013; 13(5):342-55. PMC: 4036554. DOI: 10.1038/nrc3495. View

11.

Ohyashiki J, Kobayashi C, Hamamura R, Okabe S, Tauchi T, Ohyashiki K . The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1. Cancer Sci. 2009; 100(5):970-7. PMC: 11158870. DOI: 10.1111/j.1349-7006.2009.01131.x. View

12.

Nakahira S, Nakamori S, Tsujie M, Takahashi Y, Okami J, Yoshioka S . Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer. Int J Cancer. 2006; 120(6):1355-63. DOI: 10.1002/ijc.22390. View

13.

Kontoghiorghes G, Piga A, Hoffbrand A . Cytotoxic and DNA-inhibitory effects of iron chelators on human leukaemic cell lines. Hematol Oncol. 1986; 4(3):195-204. DOI: 10.1002/hon.2900040303. View

14.

Binenbaum Y, Naara S, Gil Z . Gemcitabine resistance in pancreatic ductal adenocarcinoma. Drug Resist Updat. 2015; 23:55-68. DOI: 10.1016/j.drup.2015.10.002. View

15.

Bepler G, Kusmartseva I, Sharma S, Gautam A, Cantor A, Sharma A . RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. J Clin Oncol. 2006; 24(29):4731-7. DOI: 10.1200/JCO.2006.06.1101. View

16.

Yamasaki T, Terai S, Sakaida I . Deferoxamine for advanced hepatocellular carcinoma. N Engl J Med. 2011; 365(6):576-8. DOI: 10.1056/NEJMc1105726. View

17.

Kalinowski D, Richardson D . The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol Rev. 2005; 57(4):547-83. DOI: 10.1124/pr.57.4.2. View

18.

Harima H, Kaino S, Takami T, Shinoda S, Matsumoto T, Fujisawa K . Deferasirox, a novel oral iron chelator, shows antiproliferative activity against pancreatic cancer in vitro and in vivo. BMC Cancer. 2016; 16:702. PMC: 5007806. DOI: 10.1186/s12885-016-2744-9. View

19.

Le N, Richardson D . The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim Biophys Acta. 2002; 1603(1):31-46. DOI: 10.1016/s0304-419x(02)00068-9. View

20.

Estrov Z, Tawa A, Wang X, Dube I, Sulh H, Cohen A . In vitro and in vivo effects of deferoxamine in neonatal acute leukemia. Blood. 1987; 69(3):757-61. View