Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 6, pp 1459–1467 | Cite as

Resveratrol induces SIRT1- and energy–stress-independent inhibition of tumor cell regrowth after low-dose platinum treatment

  • My Björklund
  • Jeanette Roos
  • Vladimir Gogvadze
  • Maria Shoshan
Original Article

Abstract

Purpose

To investigate resveratrol (RSV) as a calorie restriction (CR) mimetic potentiator of platinum-based cancer drugs.

Methods

In ovarian carcinoma cell lines, the potentiating effects of RSV were assessed in sulforhodamine B-based growth assays and clonogenic assays. Flow cytometry was used to detect cell cycle effects, siRNA transfections for determining the involvement of SIRT1, and Western blotting for the assessment of altered protein expression and of autophagy. Intracellular ATP levels were detected with a commercial kit.

Results

Single-dose RSV co-treatment with cisplatin or carboplatin at inefficiently low doses had the clinically interesting effect of preventing regrowth of cancer cells after drug withdrawal. Of three cell lines tested, metastatic cells with low bioenergetic cellular index (i.e., more glycolytic) were particularly sensitive to combination treatment leading to PUMA induction, acute apoptosis, and autophagy. However, inhibition of regrowth and complete loss of clonogenicity was seen also without these events, in other cells. The underlying mechanism(s) was independent of effects reported to underlie the CR-mimetic cancer-preventive potential of RSV. Thus, SIRT1, estrogen receptors, AMPK activation or upregulation of mitobiogenesis, β-F1-ATPase or PTEN were not involved, and ATP levels did not decrease.

Conclusions

RSV is an excellent candidate for potentiation of platinum treatment, rather than a cancer therapeutic drug in its own right. While SIRT1-dependent and lifespan-promoting effects of RSV are well-documented and may dominate in normal cells, the observed potentiation of platinum drugs does not require these mechanisms. We suggest that the responses of cancer cells to RSV differ greatly from those of normal cells.

Keywords

Chemotherapy Platinum Resveratrol SIRT1 Ovarian carcinoma 

Notes

Acknowledgments

This study was supported by the Swedish Cancer Society, Radiumhemmet Research Foundation, Olle Engkvist Byggmästare and Sigurd and Elsa Golje Foundations. Linnéa Björklund is gratefully acknowledged for photography, and Drs. Theocharis Panaretakis and Pedram Kharaziha for technical advice.

Conflict of interest

None.

Supplementary material

280_2011_1640_MOESM1_ESM.pdf (47.3 mb)
Supplementary material 1 (PDF 48400 kb)

References

  1. 1.
    Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL (2009) Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms. Arch Biochem Biophys 486:95–102PubMedCrossRefGoogle Scholar
  2. 2.
    Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M (2009) Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des 74:619–624PubMedCrossRefGoogle Scholar
  3. 3.
    Benitez DA, Pozo-Guisado E, Alvarez-Barrientos A, Fernandez-Salguero PM, Castellon EA (2007) Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines. J Androl 28:282–293PubMedCrossRefGoogle Scholar
  4. 4.
    Benitez DA, Pozo-Guisado E, Clementi M, Castellon E, Fernandez-Salguero PM (2007) Non-genomic action of resveratrol on androgen and oestrogen receptors in prostate cancer: modulation of the phosphoinositide 3-kinase pathway. Br J Cancer 96:1595–1604PubMedCrossRefGoogle Scholar
  5. 5.
    Bishayee A (2009) Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res (Phila Pa) 2:409–418CrossRefGoogle Scholar
  6. 6.
    Brisdelli F, D’Andrea G, Bozzi A (2009) Resveratrol: a natural polyphenol with multiple chemopreventive properties. Curr Drug Metab 10:530–546PubMedGoogle Scholar
  7. 7.
    Brooks CL, Gu W (2009) How does SIRT1 affect metabolism, senescence and cancer? Nat Rev Cancer 9:123–128PubMedCrossRefGoogle Scholar
  8. 8.
    Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, Rahman I (2010) Regulation of SIRT1 in cellular functions: Role of polyphenols. Arch Biochem BiophysGoogle Scholar
  9. 9.
    Cuezva JM, Krajewska M, de Heredia ML, Krajewski S, Santamaria G, Kim H, Zapata JM, Marusawa H, Chamorro M, Reed JC (2002) The bioenergetic signature of cancer: a marker of tumor progression. Cancer Res 62:6674–6681PubMedGoogle Scholar
  10. 10.
    Fulda S, Galluzzi L, Kroemer G (2010) Targeting mitochondria for cancer therapy. Nat Rev Drug Discov 9:447–464PubMedCrossRefGoogle Scholar
  11. 11.
    Gledhill JR, Montgomery MG, Leslie AG, Walker JE (2007) Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc Natl Acad Sci USA 104:13632–13637PubMedCrossRefGoogle Scholar
  12. 12.
    Hernlund E, Hjerpe E, Avall-Lundqvist E, Shoshan M (2009) Ovarian carcinoma cells with low levels of beta-F1-ATPase are sensitive to combined platinum and 2-deoxy-d-glucose treatment. Mol Cancer Ther 8:1916–1923PubMedCrossRefGoogle Scholar
  13. 13.
    Isidoro A, Martinez M, Fernandez PL, Ortega AD, Santamaria G, Chamorro M, Reed JC, Cuezva JM (2004) Alteration of the bioenergetic phenotype of mitochondria is a hallmark of breast, gastric, lung and oesophageal cancer. Biochem J 378:17–20PubMedCrossRefGoogle Scholar
  14. 14.
    Klinge CM (2008) Estrogenic control of mitochondrial function and biogenesis. J Cell Biochem 105:1342–1351PubMedCrossRefGoogle Scholar
  15. 15.
    Kueck A, Opipari AW Jr, Griffith KA, Tan L, Choi M, Huang J, Wahl H, Liu JR (2007) Resveratrol inhibits glucose metabolism in human ovarian cancer cells. Gynecol Oncol 107:450–457PubMedCrossRefGoogle Scholar
  16. 16.
    Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122PubMedCrossRefGoogle Scholar
  17. 17.
    Landen CN Jr, Birrer MJ, Sood AK (2008) Early events in the pathogenesis of epithelial ovarian cancer. J Clin Oncol 26:995–1005PubMedCrossRefGoogle Scholar
  18. 18.
    Lin CS, Wang LS, Tsai CM, Wei YH (2008) Low copy number and low oxidative damage of mitochondrial DNA are associated with tumor progression in lung cancer tissues after neoadjuvant chemotherapy. Interact Cardiovasc Thorac Surg 7:954–958PubMedCrossRefGoogle Scholar
  19. 19.
    Lin PC, Lin JK, Yang SH, Wang HS, Li AF, Chang SC (2008) Expression of beta-F1-ATPase and mitochondrial transcription factor A and the change in mitochondrial DNA content in colorectal cancer: clinical data analysis and evidence from an in vitro study. Int J Colorectal Dis 23:1223–1232PubMedCrossRefGoogle Scholar
  20. 20.
    Majewski N, Nogueira V, Robey RB, Hay N (2004) Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol Cell Biol 24:730–740PubMedCrossRefGoogle Scholar
  21. 21.
    Martin-Castillo B, Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA (2010) Metformin and cancer: Doses, mechanisms and the dandelion and hormetic phenomena. Cell Cycle 9:1057–1064PubMedCrossRefGoogle Scholar
  22. 22.
    Mizushima N, Yoshimori T (2007) How to interpret LC3 immunoblotting. Autophagy 3:542–545PubMedGoogle Scholar
  23. 23.
    Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N, Madeo F, Kroemer G (2009) Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging (Albany NY) 1:961–970Google Scholar
  24. 24.
    Morselli E, Maiuri MC, Markaki M, Megalou E, Pasparaki A, Palikaras K, Criollo A, Galluzzi L, Malik SA, Vitale I, Michaud M, Madeo F, Tavernarakis N, Kroemer G (2010) The life span-prolonging effect of sirtuin-1 is mediated by autophagy. Autophagy 6:186–188PubMedCrossRefGoogle Scholar
  25. 25.
    Pizarro JG, Verdaguer E, Ancrenaz V, Junyent F, Sureda F, Pallas M, Folch J, Camins A (2011) Resveratrol inhibits proliferation and promotes apoptosis of neuroblastoma cells: role of sirtuin 1. Neurochem Res 36:187–194PubMedCrossRefGoogle Scholar
  26. 26.
    Puissant A, Robert G, Fenouille N, Luciano F, Cassuto JP, Raynaud S, Auberger P (2010) Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res 70:1042–1052PubMedCrossRefGoogle Scholar
  27. 27.
    Qian W, Nishikawa M, Haque AM, Hirose M, Mashimo M, Sato E, Inoue M (2005) Mitochondrial density determines the cellular sensitivity to cisplatin-induced cell death. Am J Physiol Cell Physiol 289:C1466–C1475PubMedCrossRefGoogle Scholar
  28. 28.
    Sanchez-Arago M, Chamorro M, Cuezva JM (2010) Selection of cancer cells with repressed mitochondria triggers colon cancer progression. Carcinogenesis 31:567–576PubMedCrossRefGoogle Scholar
  29. 29.
    Shaw RJ (2006) Glucose metabolism and cancer. Curr Opin Cell Biol 18:598–608PubMedCrossRefGoogle Scholar
  30. 30.
    Shin YK, Yoo BC, Chang HJ, Jeon E, Hong SH, Jung MS, Lim SJ, Park JG (2005) Down-regulation of mitochondrial F1F0-ATP synthase in human colon cancer cells with induced 5-fluorouracil resistance. Cancer Res 65:3162–3170PubMedGoogle Scholar
  31. 31.
    Smolkova K, Plecita-Hlavata L, Bellance N, Benard G, Rossignol R, Jezek P (2010) Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell BiolGoogle Scholar
  32. 32.
    Tyagi A, Singh RP, Agarwal C, Siriwardana S, Sclafani RA, Agarwal R (2005) Resveratrol causes Cdc2-tyr15 phosphorylation via ATM/ATR-Chk1/2-Cdc25C pathway as a central mechanism for S phase arrest in human ovarian carcinoma Ovcar-3 cells. Carcinogenesis 26:1978–1987PubMedCrossRefGoogle Scholar
  33. 33.
    Ventura-Clapier R, Garnier A, Veksler V (2008) Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res 79:208–217PubMedCrossRefGoogle Scholar
  34. 34.
    Waite KA, Sinden MR, Eng C (2005) Phytoestrogen exposure elevates PTEN levels. Hum Mol Genet 14:1457–1463PubMedCrossRefGoogle Scholar
  35. 35.
    White E, DiPaola RS (2009) The double-edged sword of autophagy modulation in cancer. Clin Cancer Res 15:5308–5316PubMedCrossRefGoogle Scholar
  36. 36.
    Yaginuma Y, Westphal H (1992) Abnormal structure and expression of the p53 gene in human ovarian carcinoma cell lines. Cancer Res 52:4196–4199PubMedGoogle Scholar
  37. 37.
    Yee KS, Wilkinson S, James J, Ryan KM, Vousden KH (2009) PUMA- and Bax-induced autophagy contributes to apoptosis. Cell Death Differ 16:1135–1145PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • My Björklund
    • 1
  • Jeanette Roos
    • 1
  • Vladimir Gogvadze
    • 2
  • Maria Shoshan
    • 1
  1. 1.Department of Oncology-Pathology, Cancer Center KarolinskaKarolinska InstitutetStockholmSweden
  2. 2.Institute of Environmental Medicine (IMM)Karolinska InstitutetStockholmSweden

Personalised recommendations