CoChat
Sign Up
Cited by 37Adrenal and Paraganglionic TumorsNeuroblastoma Research and TreatmentsRenal cell carcinoma treatment

Anthracyclines suppress pheochromocytoma cell characteristics, including metastasis, through inhibition of the hypoxia signaling pathway

Open access
Pang, Ying, Yang, Chunzhang, Schovanek, Jan, Wang, Herui, Bullova, Petra, Caisova, Veronika, Gupta, Garima, Wolf, Katherine I. +3 more·2017·Oncotarget
DOI 10.18632/oncotarget.16224PMC PMC5410225
Open this paper in CoChat — free account

Abstract

// Ying Pang 1 , Chunzhang Yang 2 , Jan Schovanek 3 , Herui Wang 4 , Petra Bullova 5 , Veronika Caisova 1 , Garima Gupta 1 , Katherine I. Wolf 1 , Gregg L. Semenza 6 , Zhengping Zhuang 4 and Karel Pacak 1 1 Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA 2 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA 3 Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic 4 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA 5 Department of Molecular Medicine, Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic 6 McKusick-Nathans Institute of Genetic Medicine and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Correspondence to: Karel Pacak, email: // Keywords : anthracyclines, paraganglioma, pheochromocytoma, metastatic, hypoxia-inducible factors Received : January 13, 2017 Accepted : March 03, 2017 Published : March 15, 2017 Abstract Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, neuroendocrine tumors derived from adrenal or extra-adrenal chromaffin cells, respectively. Metastases are discovered in 3-36% of patients at the time of diagnosis. Currently, only suboptimal treatment options exist. Therefore, new therapeutic compounds targeting metastatic PHEOs/PGLs are urgently needed. Here, we investigated if anthracyclines were able to suppress the progression of metastatic PHEO. We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin ( EPO ), phosphoglycerate kinase 1 ( PGK1 ), endothelin 1 ( EDN1 ), glucose transporter 1 ( GLUT1 ), lactate dehydrogenase A ( LDHA ), and vascular endothelial growth factor ( VEGFA ), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A . Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo . Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.18632/oncotarget.16224

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Anthracyclines, including doxorubicin, daunorubicin, epirubicin, and idarubicin, disrupt binding of HIF-1α and HIF-2α to DNA.

    “Anthracyclines, including doxorubicin, daunorubicin, epirubicin, and idarubicin, disrupt binding of HIF-1α and HIF-2α to DNA [393,394].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [394]

    The Results section ('Anthracyclines suppress transcriptional activity by blocking binding of HIFs to DNA'; page unavailable) reports that doxorubicin, epirubicin, and idarubicin inhibited HIF-1α and HIF-2α binding to target-gene DNA. The Introduction names daunorubicin as an anthracycline but says the study assessed only the other three; our copy does not establish the claimed DNA-binding effect for daunorubicin. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 49 · Cited by 37

Research works printed but not linked: 42

  1. [3]Averbuch SD Steakley CS Young RC Gelmann EP Goldstein DS Stull R Keiser HR Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine Ann Intern Med 1988 109 267 73 3395037
  2. [4]Tanabe A Naruse M Nomura K Tsuiki M Tsumagari A Ichihara A Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine in patients with malignant pheochromocytoma and paraganglioma Horm Cancer 2013 4 103 10 10.1007/s12672-013-0133-2 23361939 PMC10358011 · DOI
  3. [5]Harris AL Hypoxia—a key regulatory factor in tumour growth Nat Rev Cancer 2002 2 38 47 10.1038/nrc704 11902584 · DOI · Paper page
  4. [6]Hockel M Vaupel P Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects J Natl Cancer Inst 2001 93 266 76 10.1093/jnci/93.4.266 11181773 · DOI · Paper page
  5. [7]Brown JM Tumor hypoxia in cancer therapy Methods Enzymol 2007 435 297 321 10.1016/s0076-6879(07)35015-5 17998060 · DOI
  6. [8]Kumar V Gabrilovich DI Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment Immunology 2014 143 512 9 10.1111/imm.12380 25196648 PMC4253499 · DOI · Paper page
  7. [9]Amelio I Melino G The p53 family and the hypoxia-inducible factors (HIFs): determinants of cancer progression Trends Biochem Sci 2015 40 425 34 10.1016/j.tibs.2015.04.007 26032560 · DOI
  8. [10]Semenza GL The hypoxic tumor microenvironment: A driving force for breast cancer progression Biochim Biophys Acta 2016 1863 382 91 10.1016/j.bbamcr.2015.05.036 26079100 PMC4678039 · DOI · Paper page
  9. [12]Semenza GL Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology Annu Rev Pathol 2014 9 47 71 10.1146/annurev-pathol-012513-104720 23937437 · DOI
  10. [13]Holmquist-Mengelbier L Fredlund E Lofstedt T Noguera R Navarro S Nilsson H Pietras A Vallon-Christersson J Borg A Gradin K Poellinger L Pahlman S Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype Cancer Cell 2006 10 413 23 10.1016/j.ccr.2006.08.026 17097563 · DOI · Paper page
  11. [14]Jochmanova I Zelinka T Widimsky J Jr Pacak K HIF signaling pathway in pheochromocytoma and other neuroendocrine tumors Physiol Res 2014 63 Suppl 2 S251 62 24908231
  12. [15]Toledo RA Qin Y Srikantan S Morales NP Li Q Deng Y Kim SW Pereira MA Toledo SP Su X Aguiar RC Dahia PL In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas Endocr Relat Cancer 2013 20 349 59 10.1530/erc-13-0101 23533246 PMC5944295 · DOI
  13. [17]Yang C Sun MG Matro J Huynh TT Rahimpour S Prchal JT Lechan R Lonser R Pacak K Zhuang Z Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas Blood 2013 121 2563 6 10.1182/blood-2012-10-460972 23361906 PMC3612863 · DOI
  14. [19]Lee K Qian DZ Rey S Wei H Liu JO Semenza GL Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells Proc Natl Acad Sci U S A 2009 106 2353 8 10.1073/pnas.0812801106 19168635 PMC2650160 · DOI · Paper page
  15. [20]Yamazaki Y Hasebe Y Egawa K Nose K Kunimoto S Ikeda D Anthracyclines, small-molecule inhibitors of hypoxia-inducible factor-1 alpha activation Biol Pharm Bull 2006 29 1999 2003 17015940
  16. [21]Kaklamani VG Gradishar WJ Epirubicin versus doxorubicin: which is the anthracycline of choice for the treatment of breast cancer? Clin Breast Cancer 2003 4 Suppl 1 S26 33 12756076
  17. [23]Nakane M Takahashi S Sekine I Fukui I Koizumi M Kage K Ito Y Aiba K Horikoshi N Hatake K Ishikawa Y Ogata E Successful treatment of malignant pheochromocytoma with combination chemotherapy containing anthracycline Ann Oncol 2003 14 1449 51 12954587
  18. [24]Yang C Zhuang Z Fliedner SM Shankavaram U Sun MG Bullova P Zhu R Elkahloun AG Kourlas PJ Merino M Kebebew E Pacak K Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia J Mol Med (Berl) 2015 93 93 104 10.1007/s00109-014-1205-7 25263965 · DOI
  19. [26]Semenza GL Regulation of vascularization by hypoxia-inducible factor 1 Ann N Y Acad Sci 2009 1177 2 8 10.1111/j.1749-6632.2009.05032.x 19845601 · DOI
  20. [27]Dal Ben D Palumbo M Zagotto G Capranico G Moro S DNA topoisomerase II structures and anthracycline activity: insights into ternary complex formation Curr Pharm Des 2007 13 2766 80 17897022
  21. [28]Inge TH Harris NL Wu J Azizkhan RG Priebe W WP744 is a novel anthracycline with enhanced activity against neuroblastoma J Surg Res 2004 121 187 96 10.1016/j.jss.2004.03.027 15501458 · DOI
  22. [29]Lorenz K Brauckhoff M Behrmann C Sekulla C Ukkat J Brauckhoff K Gimm O Dralle H Selective arterial chemoembolization for hepatic metastases from medullary thyroid carcinoma Surgery 2005 138 986 93 discussion 93 10.1016/j.surg.2005.09.020 16360382 · DOI
  23. [30]Kumar P Bryant T Breen D Stedman B Hacking N Transarterial embolization and doxorubicin eluting beads-transarterial chemoembolization (DEB-TACE) of malignant extra-adrenal pheochromocytoma Cardiovasc Intervent Radiol 2011 34 1325 9 10.1007/s00270-011-0137-7 21437761 · DOI
  24. [31]Semenza GL Involvement of hypoxia-inducible factor 1 in human cancer Intern Med 2002 41 79 83 11868612
  25. [32]Safran M Kim WY O'Connell F Flippin L Gunzler V Horner JW Depinho RA Kaelin WG Jr Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production Proc Natl Acad Sci U S A 2006 103 105 10 10.1073/pnas.0509459103 16373502 PMC1324998 · DOI · Paper page
  26. [33]Bishop T Ratcliffe PJ HIF hydroxylase pathways in cardiovascular physiology and medicine Circ Res 2015 117 65 79 10.1161/circresaha.117.305109 26089364 PMC4501273 · DOI
  27. [34]Semenza GL HIF-1 and tumor progression: pathophysiology and therapeutics Trends Mol Med 2002 8 S62 7 11927290
  28. [35]Welsh SJ Powis G Hypoxia inducible factor as a cancer drug target Curr Cancer Drug Targets 2003 3 391 405 14683498
  29. [36]Brouwers FM Petricoin EF 3rd Ksinantova L Breza J Rajapakse V Ross S Johann D Mannelli M Shulkin BL Kvetnansky R Eisenhofer G Walther MM Hitt BA Low molecular weight proteomic information distinguishes metastatic from benign pheochromocytoma Endocr Relat Cancer 2005 12 263 72 10.1677/erc.1.00913 15947101 · DOI
  30. [37]Favier J Gimenez-Roqueplo AP Pheochromocytomas: the (pseudo)-hypoxia hypothesis Best Pract Res Clin Endocrinol Metab 2010 24 957 68 10.1016/j.beem.2010.10.004 21115164 · DOI
  31. [38]Lorenzo FR Yang C Tang Ng Fui M Vankayalapati H Zhuang Z Huynh T Grossmann M Pacak K Prchal JT A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma J Mol Med (Berl) 2013 91 507 12 10.1007/s00109-012-0967-z 23090011 PMC3570726 · DOI · Paper page
  32. [39]Comino-Mendez I de Cubas AA Bernal C Alvarez-Escola C Sanchez-Malo C Ramirez-Tortosa CL Pedrinaci S Rapizzi E Ercolino T Bernini G Bacca A Leton R Pita G Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis Hum Mol Genet 2013 22 2169 76 10.1093/hmg/ddt069 23418310 · DOI · Paper page
  33. [40]Tanaka T Yamaguchi J Shoji K Nangaku M Anthracycline inhibits recruitment of hypoxia-inducible transcription factors and suppresses tumor cell migration and cardiac angiogenic response in the host J Biol Chem 2012 287 34866 82 10.1074/jbc.M112.374587 22908232 PMC3471702 · DOI · Paper page
  34. [41]Weiss RB Sarosy G Clagett-Carr K Russo M Leyland-Jones B Anthracycline analogs: the past, present, and future Cancer Chemother Pharmacol 1986 18 185 97 2948729
  35. [42]Liu Y Chen F Wang S Guo X Shi P Wang W Xu B Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors Cell Death Dis 2013 4 e948 10.1038/cddis.2013.467 24309935 PMC3877540 · DOI
  36. [43]Shaul P Frenkel M Goldstein EB Mittelman L Grunwald A Ebenstein Y Tsarfaty I Fridman M The structure of anthracycline derivatives determines their subcellular localization and cytotoxic activity ACS Med Chem Lett 2013 4 323 8 10.1021/ml3002852 24900668 PMC4027571 · DOI
  37. [44]Sadurska E Current Views on Anthracycline Cardiotoxicity in Childhood Cancer Survivors Pediatr Cardiol 2015 36 1112 9 10.1007/s00246-015-1176-7 25939787 PMC4495714 · DOI
  38. [45]Barry E Alvarez JA Scully RE Miller TL Lipshultz SE Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management Expert Opin Pharmacother 2007 8 1039 58 10.1517/14656566.8.8.1039 17516870 · DOI
  39. [46]Barrett-Lee PJ Dixon JM Farrell C Jones A Leonard R Murray N Palmieri C Plummer CJ Stanley A Verrill MW Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk Ann Oncol 2009 20 816 27 10.1093/annonc/mdn728 19153118 · DOI
  40. [47]Minotti G Menna P Salvatorelli E Cairo G Gianni L Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity Pharmacol Rev 2004 56 185 229 10.1124/pr.56.2.6 15169927 · DOI
  41. [48]Fliedner SM Yang C Thompson E Abu-Asab M Hsu CM Lampert G Eiden L Tischler AS Wesley R Zhuang Z Lehnert H Pacak K Potential therapeutic target for malignant paragangliomas: ATP synthase on the surface of paraganglioma cells Am J Cancer Res 2015 5 1558 70 26101719 PMC4473332
  42. [49]Giubellino A Shankavaram U Bullova P Schovanek J Zhang Y Shen M Patel N Elkahloun A Lee MJ Trepel J Ferrer M Pacak K High-throughput screening for the identification of new therapeutic options for metastatic pheochromocytoma and paraganglioma PLoS One 2014 9 e90458 10.1371/journal.pone.0090458 24699253 PMC3974653 · DOI

Authors
Pang, Y., Yang, C., Schovanek, J., Wang, H., Bullova, P., Caisova, V., Gupta, G., Wolf, K. I., Semenza, G. L., Zhuang, Z., & Pacak, K.
Affiliations
  • National Institutes of Health (US)
  • National Cancer Institute (US)
  • Department of Internal Medicine III-Nephrology, Rheumatology, and Endocrinology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
  • Slovak Academy of Sciences (SK)
  • Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
  • Johns Hopkins University (US)
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2017-03-15
Volume
8
Issue
14
Pages
22313-22324
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.16224
PMC
PMC5410225
OpenAlex
W2603162069
Cited by
37
References
49
Citations by year
2026: 1 · 2025: 1 · 2024: 8 · 2023: 3 · 2021: 9 · 2020: 6 · 2019: 3 · 2018: 4 · 2017: 1
FWCI
3.92
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Child Health and Human Development
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
Topics
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
Keywords
anthracyclines, idarubicin, pheochromocytoma, paraganglioma, metastasis, hypoxia signaling, HIF-1, HIF-2, HIF-1α, HIF-2α, ARNT
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Adrenal Gland Neoplasms, Animals, Hypoxia, Antineoplastic Agents, Erythropoietin, Humans, Mice, Nude, Neoplasm Metastasis, Pheochromocytoma, Phosphoglycerate Kinase, Protein Binding, Idarubicin, Signal Transduction, Endothelin-1, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Growth Processes, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Hypoxia-Inducible Factor 1, alpha Subunit

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review