Skip to main content

Advertisement

SpringerLink
Log in

Gemcitabine potentiates anti-tumor effect of resveratrol on pancreatic cancer via down-regulation of VEGF-B

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

In our previous study, we discovered that resveratrol (RSV) had potential tumor-promoting effect on pancreatic cancer (PaCa) via up-regulation of VEGF-B. Therefore, we assumed that a pharmacological inhibitor of VEGF-B should potentiate the anti-tumor effect of RSV on PaCa.

Methods

Real-time PCR and western blotting were used to examine VEGF-B mRNA and protein levels. Cell viability and cell apoptosis were assessed by CCK-8 assay and flow cytometry analysis, respectively. PaCa cell-bearing nude mice were used to evaluate the anti-cancer effects of single treatment or co-administration of RSV and gemcitabine (GEM).

Results

We found that treatment with GEM alone dramatically decreased VEGF-B expression in comparison with control group, indicating that GEM is a potential pharmacological inhibitor of VEGF-B in PaCa. The co-administration of RSV and GEM significantly lowered expression of VEGF-B and increased phosphorylation level of GSK3β at Ser9 when compared to RSV alone treatment either in vitro or in vivo. Combination of RSV and GEM significantly increased cell death and apoptosis of PaCa cells in vitro and inhibited tumor growth in vivo in comparison with RSV or GEM alone treatment. Furthermore, we found that the anti-tumor effect in combination group was dramatically weakened after VEGF-B overexpressed in PaCa cells.

Conclusion

These results suggest that VEGF-B signaling pathway plays an important role in the development of PaCa and combination of GEM and RSV would be a promising modality for clinical PaCa therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

Not applicable.

Code availability

Not applicable.

References

  • Alharris E, Alghetaa H, Seth R, Chatterjee S, Singh NP, Nagarkatti M, Nagarkatti P (2018) Resveratrol attenuates allergic asthma and associated inflammation in the lungs through regulation of miRNA-34a that targets FoxP3 in mice. Front Immunol 9:2992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andreani C, Bartolacci C, Wijnant K, Crinelli R, Bianchi M, Magnani M et al (2017) Resveratrol fuels HER2 and ERα-positive breast cancer behaving as proteasome inhibitor. Aging (Albany NY) 9(2):508–523

    Article  CAS  Google Scholar 

  • Anisimov A, Leppänen VM, Tvorogov D, Zarkada G, Jeltsch M, Holopainen T et al (2013) The basis for the distinct biological activities of vascular endothelial growth factor receptor-1 ligands. Sci Signal 6(282):ra52

    Article  PubMed  CAS  Google Scholar 

  • Anisimov A, Tvorogov D, Alitalo A (2013) Vascular endothelial growth factor-angiopoietin chimera with improved properties for therapeutic angiogenesis. Circulation 127(4):424–434

    Article  CAS  PubMed  Google Scholar 

  • Apte RS, Chen DS, Ferrara N (2019) VEGF in signaling and disease: beyond discovery and development. Cell 176(6):1248–1264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bapiro TE, Richards FM, Goldgraben MA, Olive KP, Madhu B, Frese KK et al (2011) A novel method for quantification of gemcitabine and its metabolites 2’,2’-difluorodeoxyuridine and gemcitabine triphosphate in tumour tissue by LC-MS/MS: comparison with (19)F NMR spectroscopy. Cancer Chemother Pharmacol 68(5):1243–1253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U et al (2007) Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products in human multiple myeloma cells. Blood 109(6):2293–2302

    Article  CAS  PubMed  Google Scholar 

  • Bry M, Kivelä R, Leppänen V-M, Alitalo K (2014) Vascular endothelial growth factor-B in physiology and disease. Physiol Rev 94(3):779–794

    Article  CAS  PubMed  Google Scholar 

  • Chen L, Yang S, Zumbrun EE, Guan H, Nagarkatti PS, Nagarkatti M (2015) Resveratrol attenuates lipopolysaccharide-induced acute kidney injury by suppressing inflammation driven by macrophages. Mol Nutr Food Res 59(5):853–864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen C, Zou LX, Lin QY, Yan X, Bi HL, Xie X et al (2019) Resveratrol as a new inhibitor of immunoproteasome prevents PTEN degradation and attenuates cardiac hypertrophy after pressure overload. Redox Biol 20:390–401

    Article  CAS  PubMed  Google Scholar 

  • Cheng L, Yan B, Chen K, Jiang Z, Zhou C, Cao J et al (2018) Resveratrol-induced downregulation of NAF-1 enhances the sensitivity of pancreatic cancer cells to gemcitabine via the ROS/Nrf2 signaling pathways. Oxid Med Cell Longev 2018:9482018

    PubMed  PubMed Central  Google Scholar 

  • Cole A, Frame S, Cohen P (2004) Further evidence that the tyrosine phosphorylation of glycogen synthase kinase-3 (GSK3) in mammalian cells is an autophosphorylation event. Biochem J 377(Pt 1):249–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deus CM, Serafim TL, Magalhães-Novais S, Vilaça A, Moreira AC, Sardão VA et al (2017) Sirtuin 1-dependent resveratrol cytotoxicity and pro-differentiation activity on breast cancer cells. Arch Toxicol 91(3):1261–1278

    Article  CAS  PubMed  Google Scholar 

  • Elkin M, Orgel A, Kleinman HK (2004) An angiogenic switch in breast cancer involves estrogen and soluble vascular endothelial growth factor receptor 1. J Natl Cancer Inst 96(11):875–878

    Article  CAS  PubMed  Google Scholar 

  • Falkevall A, Mehlem A, Palombo I, Heller Sahlgren B, Ebarasi L, He L et al (2017) Reducing VEGF-B signaling ameliorates renal lipotoxicity and protects against diabetic kidney disease. Cell Metab 25(3):713–726

    Article  CAS  PubMed  Google Scholar 

  • Feng L, Ren J, Li Y, Yang G, Kang L, Zhang S et al (2019) Resveratrol protects against isoproterenol induced myocardial infarction in rats through VEGF-B/AMPK/eNOS/NO signalling pathway. Free Radic Res 53(1):82–93

    Article  CAS  PubMed  Google Scholar 

  • Folbergrová J, Ješina P, Kubová H, Otáhal J (2018) Effect of resveratrol on oxidative stress and mitochondrial dysfunction in immature brain during epileptogenesis. Mol Neurobiol 55(9):7512–7522

    Article  PubMed  CAS  Google Scholar 

  • Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I et al (2010) Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464(7290):917–921

    Article  CAS  PubMed  Google Scholar 

  • Hagberg CE, Mehlem A, Falkevall A, Muhl L, Fam BC, Ortsäter H et al (2012) Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature 490(7420):426–430

    Article  CAS  PubMed  Google Scholar 

  • Hanrahan V, Currie MJ, Gunningham SP, Morrin HR, Scott PA, Robinson BA, Fox SB (2003) The angiogenic switch for vascular endothelial growth factor (VEGF)-A, VEGF-B, VEGF-C, and VEGF-D in the adenoma-carcinoma sequence during colorectal cancer progression. J Pathol 200(2):183–194

    Article  CAS  PubMed  Google Scholar 

  • Huminiecki L, Horbanczuk J (2018) The functional genomic studies of resveratrol in respect to its anti-cancer effects. Biotechnol Adv 36(6):1699–1708

    Article  CAS  PubMed  Google Scholar 

  • Jiang Z, Chen X, Chen K, Sun L, Gao L, Zhou C et al (2016) YAP inhibition by resveratrol via activation of AMPK enhances the sensitivity of pancreatic cancer cells to gemcitabine. Nutrients 8(10):546

    Article  PubMed Central  CAS  Google Scholar 

  • Kim YN, Choe SR, Cho KH, Cho DY, Kang J, Park CG, Lee HY (2017) Resveratrol suppresses breast cancer cell invasion by inactivating a RhoA/YAP signaling axis. Exp Mol Med 49(2):e296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kivelä R, Bry M, Robciuc MR, Räsänen M, Taavitsainen M, Silvola JMU et al (2014) VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart. EMBO Mol Med 6(3):307–321

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV et al (2016) Pancreatic cancer. Nat Rev Dis Primers 2:16022

    Article  PubMed  Google Scholar 

  • Matsumura N, Takahara S, Maayah ZH, Parajuli N, Byrne NJ, Shoieb SM et al (2018) Resveratrol improves cardiac function and exercise performance in MI-induced heart failure through the inhibition of cardiotoxic HETE metabolites. J Mol Cell Cardiol 125:162–173

    Article  CAS  PubMed  Google Scholar 

  • Minami K, Shinsato Y, Yamamoto M, Takahashi H, Zhang S, Nishizawa Y et al (2015) Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors. J Pharmacol Sci 127(3):319–325

    Article  CAS  PubMed  Google Scholar 

  • Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H et al (2004) A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350(12):1200–1210

    Article  CAS  PubMed  Google Scholar 

  • Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K et al (2013) Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 310(14):1473–1481

    Article  CAS  PubMed  Google Scholar 

  • Reymond N, d'Água BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13(12):858–870

    Article  CAS  PubMed  Google Scholar 

  • Rivière C, Pawlus AD, Mérillon JM (2012) Natural stilbenoids: distribution in the plant kingdom and chemotaxonomic interest in Vitaceae. Nat Prod Rep 29(11):1317–1333

    Article  PubMed  CAS  Google Scholar 

  • Samulitis BK, Pond KW, Pond E, Cress AE, Patel H, Wisner L et al (2015) Gemcitabine resistant pancreatic cancer cell lines acquire an invasive phenotype with collateral hypersensitivity to histone deacetylase inhibitors. Cancer Biol Ther 16(1):43–51

    Article  CAS  PubMed  Google Scholar 

  • Serpi R, Tolonen AM, Huusko J, Rysä J, Tenhunen O, Ylä-Herttuala S, Ruskoaho H (2011) Vascular endothelial growth factor-B gene transfer prevents angiotensin II-induced diastolic dysfunction via proliferation and capillary dilatation in rats. Cardiovasc Res 89(1):204–213

    Article  CAS  PubMed  Google Scholar 

  • Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69(1):7–34

    Article  PubMed  Google Scholar 

  • Sun S, Zhang M, Yang Q, Shen Z, Chen J, Yu B et al (2017) Resveratrol suppresses lipoprotein-associated phospholipase A2 expression by reducing oxidative stress in macrophages and animal models. Mol Nutr Food Res 61(10):1601112

    Article  CAS  Google Scholar 

  • Tan L, Wang W, He G, Kuick RD, Gossner G, Kueck AS et al (2016) Resveratrol inhibits ovarian tumor growth in an in vivo mouse model. Cancer 122(5):722–729

    Article  CAS  PubMed  Google Scholar 

  • Tian W, Yang L, Liu Y, He J, Yang L, Zhang Q et al (2019) Resveratrol attenuates doxorubicin-induced cardiotoxicity in rats by up-regulation of vascular endothelial growth factor B. J Nutr Biochem 79:108132

    Article  PubMed  CAS  Google Scholar 

  • Xu CP, Xue XJ, Liang N, Xu DG, Liu FJ, Yu XS, Zhang JD (2014) Effect of chemoradiotherapy and neoadjuvant chemoradiotherapy in resectable pancreatic cancer: a systematic review and meta-analysis. J Cancer Res Clin Oncol 140(4):549–559

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Yang L, Tian W, Li J, Liu J, Zhu M et al (2014) Resveratrol plays dual roles in pancreatic cancer cells. J Cancer Res Clin Oncol 140(5):749–755

    Article  CAS  PubMed  Google Scholar 

  • Yang L, Zhang Y, Zhu M, Zhang Q, Wang X, Wang Y et al (2016) Resveratrol attenuates myocardial ischemia/reperfusion injury through up-regulation of vascular endothelial growth factor B. Free Radic Biol Med 101:1–9

    Article  CAS  PubMed  Google Scholar 

  • Zhang YJ, Wen CL, Qin YX, Tang XM, Shi MM, Shen BY, Fang Y (2017) Establishment of a human primary pancreatic cancer mouse model to examine and investigate gemcitabine resistance. Oncol Rep 38(6):3335–3346

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou C, Qian W, Ma J, Cheng L, Jiang Z, Yan B et al (2019) Resveratrol enhances the chemotherapeutic response and reverses the stemness induced by gemcitabine in pancreatic cancer cells via targeting SREBP1. Cell Prolif 52(1):e12514

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Natural Science Foundation of China (No. 81971887, 81772252, 31971194 and 81801949), Tianjin Natural Science Foundation (No. 16JCYBJC28100), Key Laboratory of Emergency and Trauma (Hainan Medical University), Ministry of Education (No. KLET-201906) and Fundamental Research Funds for the Central Universities (No. 63191175).

Funding

This research was supported by the National Natural Science Foundation of China (No. 81971887, 81772252, 31971194 and 81801949), Tianjin Natural Science Foundation (No. 16JCYBJC28100), Key Laboratory of Emergency and Trauma (Hainan Medical University), Ministry of Education (No. KLET-201906) and Fundamental Research Funds for the Central Universities (No. 63191175).

Author information

Author notes

  1. Yinan Yang and Wencong Tian contributed equally to this work.

Authors and Affiliations

  1. Department of Histology and Embryology, School of Medicine, Nankai University, 94 Weijin Road, Nankai District, Tianjin, 300071, China

    Yinan Yang, Wencong Tian, Lei Yang, Mengmeng Zhu, Yuansheng Liu, Jing Li, Liang Yang, Jie Liu & Zhi Qi

  2. Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, 300100, China

    Yinan Yang

  3. Department of Microbiology, School of Laboratory Medicine, Tianjin Medical University, 1 Guangdong Road, Hexi District, Tianjin, 300203, China

    Qiong Zhang & Yanna Shen

  4. National Clinical Research Center of Kidney Diseases, Beijing, 100853, China

    Zhi Qi

Authors
  1. Yinan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wencong Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lei Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mengmeng Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuansheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Liang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jie Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yanna Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhi Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YS, ZQ: Conceptualization. WT, ZQ: Data curation. YY, LY: Formal analysis. YS, ZQ, LY, WT: Funding acquisition. YY, LY, QZ: Investigation. JL, LY, JL: Methodology. YL: Software. LY, MZ: Visualization. WT, ZQ: Writing-original draft. YS, ZQ: Writing-revising and editing.

Corresponding authors

Correspondence to Yanna Shen or Zhi Qi.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Tian, W., Yang, L. et al. Gemcitabine potentiates anti-tumor effect of resveratrol on pancreatic cancer via down-regulation of VEGF-B. J Cancer Res Clin Oncol 147, 93–103 (2021). https://doi.org/10.1007/s00432-020-03384-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-020-03384-7

Keywords

Search

Navigation