MFTZ‐1 reduces constitutive and inducible HIF‐1α accumulation and VEGF secretion independent of its topoisomerase II inhibition

Dai, Mei; Miao, Ze‐Hong; Ren, Xuan; Tong, Lin‐Jiang; Yang, Na; Li, Ting; Lin, Li‐Ping; Shen, Yue‐Mao; Ding, Jian

doi:10.1111/j.1582-4934.2009.00822.x

Cited by 16Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerCancer therapeutics and mechanisms

The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.

MFTZ‐1 reduces constitutive and inducible HIF‐1α accumulation and VEGF secretion independent of its topoisomerase II inhibition

Open access

Dai, Mei, Miao, Ze‐Hong, Ren, Xuan, Tong, Lin‐Jiang, Yang, Na, Li, Ting, Lin, Li‐Ping, Shen, Yue‐Mao, Ding, Jian·2010·Journal of Cellular and Molecular Medicine

DOI 10.1111/j.1582-4934.2009.00822.xPMC PMC3822569

Open this paper in CoChat — free account Open PDF

Abstract

The macrolide compound MFTZ‐1 has been identified as a novel topoisomerase II (Top2) inhibitor with potent in vitro and in vivo anti‐tumour activities. In this study, we further examined the effects of MFTZ‐1 on hypoxia‐inducible factor‐1α (HIF‐1α) accumulation, vascular endothelial growth factor (VEGF) secretion and angiogenesis. MFTZ‐1 reduced HIF‐1α accumulation driven by hypoxia or growth factors in human cancer cells. Mechanistic studies revealed that MFTZ‐1 did not affect the degradation of HIF‐1α protein or the level of HIF‐1α mRNA. By contrast, MFTZ‐1 apparently inhibited constitutive and inducible activation of both phosphatidylinositol‐3‐kinase (PI3K)‐Akt and p42/p44 mitogen‐activated protein kinase (MAPK) pathways. Further studies revealed that MFTZ‐1 abrogated the HIF‐1α‐driven increase in VEGF mRNA and protein secretion. MFTZ‐1 also lowered the basal level of VEGF secretion. The results reveal an important feature that MFTZ‐1 can reduce constitutive, HIF‐1α‐independent VEGF secretion and concurrently antagonize inducible, HIF‐1α‐dependent VEGF secretion. Moreover, MFTZ‐1 disrupted tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by hypoxia with low‐concentration serum or by serum at normoxia, and inhibited HUVECs migration at normoxia. MFTZ‐1 also prevented microvessel outgrowth from rat aortic ring. These data reflect the potent anti‐angiogenesis of MFTZ‐1 under different conditions. Furthermore, using specific small interfering RNA targeting Top2α or Top2‐defective HL60/MX2 cells, we showed that MFTZ‐1 affected HIF‐1α accumulation and HUVECs tube formation irrelevant to its Top2 inhibition. Taken together, our data collectively reveal that MFTZ‐1 reduces constitutive and inducible HIF‐1α accumulation and VEGF secretion possibly via PI3K‐Akt and MAPK pathways, eliciting anti‐angiogenesis independently of its Top2 inhibition.

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.

Integrity signals

Registry

Crossref · 10.1111/j.1582-4934.2009.00822.x

Cites

42 of 42 references verified0 citation errors · 0 not checkable

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.

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?

Accumulating evidence supports the conclusion that inhibition of HIF signaling by topoisomerase inhibitors occurs in a topoisomerase I- or II-dependent manner but is largely independent of their canonical cytotoxic effects.
“Accumulating evidence now supports the conclusion that inhibition of HIF signaling by these agents occurs in a topoisomerase I- or II-dependent manner [309,310] but is largely independent of their canonical cytotoxic effects [311].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [311]

Self-check

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

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

Targeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
Hypoxia-Inducible Factor-1 (HIF-1)
Ke, Q., & Costa, M. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.027029 · Cited by 1,689
HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression
Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C., & Semenza, G. L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.12.3995-4004.2001 · Cited by 1,256 · cited 1×
“Both the PI3K-Akt pathway [5, 25, 27, 28] and the MAPK pathway [6, 29] have been recently shown to control the translation of HIF-1 .”
Background
Insulin-like Growth Factor 1 Induces Hypoxia-inducible Factor 1-mediated Vascular Endothelial Growth Factor Expression, Which is Dependent on MAP Kinase and Phosphatidylinositol 3-Kinase Signaling in Colon Cancer Cells
Fukuda, R., Hirota, K., Fan, F., Jung, Y. D., Ellis, L. M., & Semenza, G. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203781200 · Cited by 830
Hypoxia: A key regulator of angiogenesis in cancer
Liao, D., & Johnson, R. S. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9066-y · Cited by 737
HIF-1 as a target for drug development
Giaccia, A., Siim, B. G., & Johnson, R. S. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1199 · Cited by 631
mTOR, translation initiation and cancer
Mamane, Y., Petroulakis, E., LeBacquer, O., & Sonenberg, N. (2006) · Oncogene · doi:10.1038/sj.onc.1209888 · Cited by 607
Untitled work
(2001) · PubMed · Cited by 557
Insulin Stimulates Hypoxia-inducible Factor 1 through a Phosphatidylinositol 3-Kinase/Target of Rapamycin-dependent Signaling Pathway
Treins, C., Giorgetti‐Peraldi, S., Murdaca, J., Semenza, G. L., & OBBERGHEN, E. V. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204152200 · Cited by 554
Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis
Tang, N., Wang, L., Esko, J. D., Giordano, F. J., Huang, Y., Gerber, H., Ferrara, N., & Johnson, R. S. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.09.026 · Cited by 549
Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia.
Sowter, H., Raval, R. R., Moore, J. W., Ratcliffe, P. J., & Harris, A. L. (2003) · PubMed · Cited by 371
Evaluation of HIF-1 inhibitors as anticancer agents
Semenza, G. L. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.08.006 · Cited by 363
Mechanisms of drug inhibition of signalling molecules
Sebolt, J. S., & English, J. M. (2006) · Nature · doi:10.1038/nature04874 · Cited by 309
1α,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells
Ben‐Shoshan, M., Amir, S., Dang, D. T., Dang, L. H., Weisman, Y., & Mabjeesh, N. J. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0677 · Cited by 243
Hypoxic induction of an HIF-1α–dependent bFGF autocrine loop drives angiogenesis in human endothelial cells
Calvani, M., Rapisarda, A., Uranchimeg, B., Shoemaker, R. H., & Melillo, G. (2005) · Blood · doi:10.1182/blood-2005-09-3541 · Cited by 231
PI3K/Akt Is Required for Heat Shock Proteins to Protect Hypoxia-inducible Factor 1α from pVHL-independent Degradation
Zhou, J., Schmid, T., Frank, R., & Brüne, B. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310164200 · Cited by 225
Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines.
Blancher, C., Moore, J. W., Talks, K., Houlbrook, S., & Harris, A. L. (2000) · PubMed · Cited by 220
Akt1 Activation Can Augment Hypoxia-Inducible Factor-1α Expression by Increasing Protein Translation through a Mammalian Target of Rapamycin–Independent Pathway
Pore, N., Jiang, Z., Shu, H. G., Bernhard, E. J., Kao, G. D., & Maity, A. M. (2006) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-05-0234 · Cited by 190
Inhibiting Hypoxia-Inducible Factor 1 for Cancer Therapy
Melillo, G. (2006) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-06-0235 · Cited by 168
Vascular endothelial growth factor, a specific regulator of angiogenesis
Ferrara, N., & Bunting, S. (1996) · Current Opinion in Nephrology & Hypertension · doi:10.1097/00041552-199601000-00008 · Cited by 165
Inhibition of Endothelial Cell Migration, Intercellular Communication, and Vascular Tube Formation by Thromboxane A2
Ashton, A. W., Yokota, R., John, G. W., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.50.35562 · Cited by 149
Philinopside a, a novel marine‐derived compound possessing dual anti‐angiogenic and anti‐tumor effects
Tong, Y., Zhang, X., Tian, F., Yi, Y., Xu, Q.-Z., Li, L., Tong, L., Lin, L., & Ding, J. (2005) · International Journal of Cancer · doi:10.1002/ijc.20804 · Cited by 109
Self-citation
Oligomannurarate Sulfate, a Novel Heparanase Inhibitor Simultaneously Targeting Basic Fibroblast Growth Factor, Combats Tumor Angiogenesis and Metastasis
Zhao, H., Liu, H., Chen, Y., Xin, X., Li, J., Hou, Y., Zhang, Z., Zhang, X., Xie, C., Geng, M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1382 · Cited by 101
Self-citation
Gambogic acid inhibits the catalytic activity of human topoisomerase IIα by binding to its ATPase domain
Qin, Y., Meng, L., Hu, C., Duan, W., Zuo, Z., Lin, L., Zhang, X., & Ding, J. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0147 · Cited by 101
Self-citation
Alterations in the topoisomerase II alpha gene, messenger RNA, and subcellular protein distribution as well as reduced expression of the DNA topoisomerase II beta enzyme in a mitoxantrone-resistant HL-60 human leukemia cell line.
Harker, W. G., Slade, D., Parr, R., et al. (1995) · PubMed · Cited by 95
Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells
Trisciuoglio, D., Iervolino, A., Zupi, G., & Bufalo, D. D. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-12-1087 · Cited by 91
Pseudolaric Acid B Inhibits Angiogenesis and Reduces Hypoxia-Inducible Factor 1α by Promoting Proteasome-Mediated Degradation
Li, M.-H., Miao, Z., Tan, W., Yue, J., Zhang, C., Lin, L., Zhang, X., & Ding, J. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-0951 · Cited by 86
Self-citation
Cisplatin and doxorubicin repress Vascular Endothelial Growth Factor expression and differentially down-regulate Hypoxia-inducible Factor I activity in human ovarian cancer cells
Duyndam, M. C. A., van Berkel, M. P. A., Dorsman, J. C., Rockx, D., Pinedo, H. M., & Boven, E. (2007) · Biochemical Pharmacology · doi:10.1016/j.bcp.2007.04.003 · Cited by 78
Tumor-specific RNAi targeting eIF4E suppresses tumor growth, induces apoptosis and enhances cisplatin cytotoxicity in human breast carcinoma cells
Dong, K., Wang, R. C., Wang, X., et al. (2008) · Breast Cancer Research and Treatment · doi:10.1007/s10549-008-9956-x · Cited by 77
R16, a novel amonafide analogue, induces apoptosis and G2-M arrest via poisoning topoisomerase II
Zhu, H., Huang, M., Yang, F., et al. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-06-0584 · Cited by 76
Constitutive/Hypoxic Degradation of HIF-α Proteins by the Proteasome Is Independent of von Hippel Lindau Protein Ubiquitylation and the Transactivation Activity of the Protein
Kong, X., Alvarez‐Castelao, B., Lin, Z., Castaño, J. G., & Caro, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700704200 · Cited by 72
Anti-angiogenic effects of SN38 (active metabolite of irinotecan): inhibition of hypoxia-inducible factor 1 alpha (HIF-1?)/vascular endothelial growth factor (VEGF) expression of glioma and growth of endothelial cells
Kamiyama, H., Takano, S., Tsuboi, K., & Matsumura, A. (2004) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-004-0642-z · Cited by 65
Expression levels of eIF4E, VEGF, and cyclin D1, and correlation of eIF4E with VEGF and cyclin D1 in multi-tumor tissue microarray
Yang, S. X., Hewitt, S. M., Steinberg, S. A., et al. (2007) · Oncology Reports · doi:10.3892/or.17.2.281 · Cited by 58
Regulation of HIF: Prolyl Hydroxylases
Stolze, I. P., Mole, D. R., & Ratcliffe, P. J. (2006) · Novartis Foundation symposium · doi:10.1002/9780470035009.ch3 · Cited by 55
IGF-1 induced vascular endothelial growth factor secretion in head and neck squamous cell carcinoma
Slomiany, M. G., Black, L., Kibbey, M. M., Day, T. A., & Rosenzweig, S. A. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.02.043 · Cited by 53
Cell Type–Specific, Topoisomerase II–Dependent Inhibition of Hypoxia-Inducible Factor-1α Protein Accumulation by NSC 644221
Creighton-Gutteridge, M., Cardellina, J. H., Stephen, A. G., Rapisarda, A., Uranchimeg, B., Hite, K. M., Denny, W. A., Shoemaker, R. H., & Melillo, G. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2301 · Cited by 51
Antibacterial and antitumor macrolides fromstreptomyces sp. Is9131
Zhao, P., Fan, L. M., Li, G. H., et al. (2005) · Archives of Pharmacal Research · doi:10.1007/bf02978203 · Cited by 47
Akt mediates an angiogenic switch in transformed keratinocytes
Segrelles, C. (2004) · Carcinogenesis · doi:10.1093/carcin/bgh132 · Cited by 43
Periodicity of DNA bend sites in human epsilon-globin gene region. Possibility of sequence-directed nucleosome phasing.
Wada‐Kiyama, Y., & Kiyama, R. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31782-9 · Cited by 34
Evaluation of active recombinant catalytic domain of human ErbB-2 tyrosine kinase, and suppression of activity by a naturally derived inhibitor, ZH-4B
Guo, X., Zhong, L., Zhang, X., et al. (2004) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2004.04.015 · Cited by 20
MFTZ-1, an actinomycetes subspecies–derived antitumor macrolide, functions as a novel topoisomerase II poison
Xie, C., Zhu, H., Lin, L., et al. (2007) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-07-0014 · Cited by 17
Self-citation
TKI-31 inhibits angiogenesis by combined suppression signaling pathway of VEGFR2 and PDGFRbeta
Li, Z., Guo, X.-N., Zhang, X., et al. (2006) · Cancer Biology & Therapy · doi:10.4161/cbt.5.3.2543 · Cited by 13

Flagged first, then by citations

Sorted by citations

Suppression of Hypoxia-Inducible Factor 1α (HIF-1α) by Tirapazamine Is Dependent on eIF2α Phosphorylation Rather Than the mTORC1/4E-BP1 Pathway
Zhang, J., Cao, J., Weng, Q., Wu, R., Yan, Y., Jing, H., Zhu, H., He, Q., & Yang, B. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013910 · Cited by 56
Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide
Zhou, Z.-L., Luo, Z.-G., Yu, B., Jiang, Y., Chen, Y., Feng, J.-M., Dai, M., Tong, L.-J., Li, Z., Li, Y.-C., et al. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-268 · Cited by 38
Self-citation
HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3
“Accumulating evidence now supports the conclusion that inhibition of HIF signaling by these agents occurs in a topoisomerase I-or II-dependent manner [309, 310] but is largely independent of their canonical cytotoxic effects [311].”

[Suppression of vascular endothelial growth factor expression by vector-based small interfering RNA in human tongue squamous carcinoma cell line Tca8113].
Yu, D., Cao, Y., Yao, Z., et al. (2008) · PubMed
The role of insulin-like growth factor I and hypoxia inducible factor 1α in vascular endothelial growth factor expression in type 2 diabetes.
Jiang, F., Tang, Y., Guo, L., & Jiao, X. (2013) · PubMed · Cited by 13
Effect of angiopoietin2,hypoxia inducible factor-1α and vascular endothelial growth factor on angiogenesis in human hepatocellular carcinoma
Ai, Z.-L. (2006) · Zhonghua putong waike zazhi
Expression of hypoxia inducible factor-1α, hypoxia inducible factor-2α and vascular endothelial growth factor in metastatic lung cancer and clinical significance
Yu, Z., Wang, R., Cai, D., et al. (2015) · Zhonghua shiyan waike zazhi · doi:10.3760/cma.j.issn.1001-9030.2015.03.067
Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy
Verheyen, A., Peeraer, E., Nuydens, R., Dhondt, J., Poesen, K., Pintelon, I., Daniels, A., Timmermans, J., Meert, T. F., Carmeliet, P., et al. (2012) · Brain · doi:10.1093/brain/aws145 · Cited by 66

Authors: Dai, M., Miao, Z., Ren, X., Tong, L., Yang, N., Li, T., Lin, L., Shen, Y., & Ding, J.
Affiliations: Chinese Academy of Sciences (CN)
Corresponding author: Miao, Ze‐Hong
Ding, Jian
ORCID: Dai, Mei
Miao, Ze‐Hong
Ren, Xuan
Li, Ting
Ding, Jian
Venue: Journal of Cellular and Molecular Medicine
Publisher: Wiley
Published: 2009-06-16
Volume: 14
Issue: 9
Pages: 2281-2291
ISSN: 1582-1838 (ISSN-L)
1582-4934
DOI: 10.1111/j.1582-4934.2009.00822.x
PMC: PMC3822569
OpenAlex: W2134349528
Cited by: 16
References: 42
Citations by year: 2026: 1 · 2020: 1 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 1 · 2012: 3
FWCI: 0.88
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Journal of Cellular and Molecular Medicine (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Natural Science Foundation of China
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
Keywords: macrolides, topoisomerase II inhibition, VEGF secretion, angiogenesis, PI3K/Akt signaling, MAPK signaling, hypoxia, tube formation, endothelial cell migration, antiangiogenic activity
MeSH terms: Animals, DNA Topoisomerases, Type II, Humans, Neovascularization, Pathologic, Protein Processing, Post-Translational, RNA, Messenger, Transcription, Genetic, Signal Transduction, Eicosanoids, Rats, Sprague-Dawley, Macrolides, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, Vascular Endothelial Growth Factor A, Endothelial Cells, Cell Line, Tumor, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-akt, Rats, Hypoxia-Inducible Factor 1, alpha Subunit, Topoisomerase II Inhibitors

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

MFTZ‐1 reduces constitutive and inducible HIF‐1α accumulation and VEGF secretion independent of its topoisomerase II inhibition

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks