Skip to main content

Advertisement

SpringerLink
Log in

Simultaneous treatment with camptothecin and valproic acid suppresses induction of Bcl-XL and promotes apoptosis of MCF-7 breast cancer cells

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Camptothecin derivatives have been widely used for chemotherapy in patients with various cancers, but intrinsic and acquired drug resistance is major drawback to be overcome. In the present study, we demonstrated that simultaneous treatment with camptothecin and valproic acid induced apoptosis of MCF-7 cells, whereas neither agent alone could efficiently induce apoptosis. This induction of apoptosis was associated with loss of the mitochondrial membrane potential and was caspase dependent. Further investigation showed that concurrent treatment modulated the expression of pro-apoptotic and anti-apoptotic genes. Bcl-XL expression was induced in MCF-7 cells treated with camptothecin alone, but not in cells treated simultaneously with camptothecin and valproic acid. Ectopic overexpression of Bcl-XL in MCF-7 cells completely suppressed the induction of apoptosis, even with simultaneous treatment. On the other hand, efficient induction of apoptosis was achieved by treatment with camptothecin and Bcl-XL inactivation (using siRNA or BH3 mimetic). The cytotoxic effect of camptothecin combined with valproic acid was more than additive for MCF-7 cells. Taken together, our results suggest that simultaneous administration of camptothecin and valproic acid might be useful for anticancer 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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Perez EA, Hillman DW, Mailliard JA et al (2004) Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 22(14):2849–2855

    Article  PubMed  CAS  Google Scholar 

  2. Stathopoulos GP, Tsavdaridis D, Malamos NA et al (2005) Irinotecan combined with docetaxel in pre-treated metastatic breast cancer patients: a phase II study. Cancer Chemother Pharmacol 56(5):487–491

    Article  PubMed  CAS  Google Scholar 

  3. Xu Y, Villalona-Calero MA (2002) Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. Ann Oncol 13(12):1841–1851

    Article  PubMed  CAS  Google Scholar 

  4. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276(39):36734–36741

    Article  PubMed  CAS  Google Scholar 

  5. Gottlicher M, Minucci S, Zhu P et al (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20(24):6969–6978

    Article  PubMed  CAS  Google Scholar 

  6. Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63(21):7291–7300

    PubMed  CAS  Google Scholar 

  7. Marchion DC, Bicaku E, Daud AI, Richon V, Sullivan DM, Munster PN (2004) Sequence-specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. J Cell Biochem 92(2):223–237

    Article  PubMed  CAS  Google Scholar 

  8. Marchion DC, Bicaku E, Daud AI, Sullivan DM, Munster PN (2005) In vivo synergy between topoisomerase II and histone deacetylase inhibitors: predictive correlates. Mol Cancer Ther 4(12):1993–2000

    Article  PubMed  CAS  Google Scholar 

  9. Devarajan E, Sahin AA, Chen JS et al (2002) Down-regulation of caspase 3 in breast cancer: a possible mechanism for chemoresistance. Oncogene 21(57):8843–8851

    Article  PubMed  CAS  Google Scholar 

  10. Winter RN, Kramer A, Borkowski A, Kyprianou N (2001) Loss of caspase-1 and caspase-3 protein expression in human prostate cancer. Cancer Res 61(3):1227–1232

    PubMed  CAS  Google Scholar 

  11. Janicke RU, Sprengart ML, Wati MR, Porter AG (1998) Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 273(16):9357–9360

    Article  PubMed  CAS  Google Scholar 

  12. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  PubMed  CAS  Google Scholar 

  13. Smiley ST, Reers M, Mottola-Hartshorn C et al (1991) Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc Natl Acad Sci USA 88(9):3671–3675

    Article  PubMed  CAS  Google Scholar 

  14. Meng Y, Tang W, Dai Y et al (2008) Natural BH3 mimetic (−)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa. Mol Cancer Ther 7(7):2192–2202

    Article  PubMed  CAS  Google Scholar 

  15. Yang XH, Sladek TL, Liu X, Butler BR, Froelich CJ, Thor AD (2001) Reconstitution of caspase 3 sensitizes MCF-7 breast cancer cells to doxorubicin- and etoposide-induced apoptosis. Cancer Res 61(1):348–354

    PubMed  CAS  Google Scholar 

  16. Bolden JE, Peart MJ, Johnstone RW (2006) Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5(9):769–784

    Article  PubMed  CAS  Google Scholar 

  17. Chobanian NH, Greenberg VL, Gass JM, Desimone CP, Van Nagell JR, Zimmer SG (2004) Histone deacetylase inhibitors enhance paclitaxel-induced cell death in ovarian cancer cell lines independent of p53 status. Anticancer Res 24(2B):539–545

    PubMed  CAS  Google Scholar 

  18. Kuendgen A, Schmid M, Schlenk R et al (2006) The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer 106(1):112–119

    Article  PubMed  CAS  Google Scholar 

  19. Adachi M, Zhang Y, Zhao X et al (2004) Synergistic effect of histone deacetylase inhibitors FK228 and m-carboxycinnamic acid bis-hydroxamide with proteasome inhibitors PSI and PS-341 against gastrointestinal adenocarcinoma cells. Clin Cancer Res 10(11):3853–3862

    Article  PubMed  CAS  Google Scholar 

  20. Peart MJ, Smyth GK, van Laar RK et al (2005) Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA 102(10):3697–3702

    Article  PubMed  CAS  Google Scholar 

  21. Rada-Iglesias A, Enroth S, Ameur A et al (2007) Butyrate mediates decrease of histone acetylation centered on transcription start sites and down-regulation of associated genes. Genome Res 17(6):708–719

    Article  PubMed  CAS  Google Scholar 

  22. Hayward RL, Macpherson JS, Cummings J, Monia BP, Smyth JF, Jodrell DI (2003) Antisense Bcl-xl down-regulation switches the response to topoisomerase I inhibition from senescence to apoptosis in colorectal cancer cells, enhancing global cytotoxicity. Clin Cancer Res 9(7):2856–2865

    PubMed  CAS  Google Scholar 

  23. Sowa Y, Orita T, Minamikawa S et al (1997) Histone deacetylase inhibitor activates the WAF1/Cip1 gene promoter through the Sp1 sites. Biochem Biophys Res Commun 241(1):142–150

    Article  PubMed  CAS  Google Scholar 

  24. Sandor V, Senderowicz A, Mertins S et al (2000) P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br J Cancer 83(6):817–825

    Article  PubMed  CAS  Google Scholar 

  25. Walker PR, Leblanc J, Carson C, Ribecco M, Sikorska M (1999) Neither caspase-3 nor DNA fragmentation factor is required for high molecular weight DNA degradation in apoptosis. Ann NY Acad Sci 887:48–59

    Article  PubMed  CAS  Google Scholar 

  26. Lakhani SA, Masud A, Kuida K et al (2006) Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311(5762):847–851

    Article  PubMed  CAS  Google Scholar 

  27. Gupta E, Wang X, Ramirez J, Ratain MJ (1997) Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital. Cancer Chemother Pharmacol 39(5):440–444

    Article  PubMed  CAS  Google Scholar 

  28. Munster P, Marchion D, Bicaku E et al (2007) Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study. J Clin Oncol 25(15):1979–1985

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Oncology and Hematology, Jikei University School of Medicine, Nishi-Shimbashi 3-25-8, Minato-ku, Tokyo, 105-8461, Japan

    Yasuhiro Arakawa & Keisuke Aiba

  2. Department of Molecular Genetics, Institute of DNA Medicine, Jikei University School of Medicine, Nishi-Shimbashi 3-25-8, Minato-ku, Tokyo, 105-8461, Japan

    Shinobu Saito & Hisashi Yamada

Authors
  1. Yasuhiro Arakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shinobu Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hisashi Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keisuke Aiba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuhiro Arakawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arakawa, Y., Saito, S., Yamada, H. et al. Simultaneous treatment with camptothecin and valproic acid suppresses induction of Bcl-XL and promotes apoptosis of MCF-7 breast cancer cells. Apoptosis 14, 1076–1085 (2009). https://doi.org/10.1007/s10495-009-0384-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-009-0384-0

Keywords

Search

Navigation