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Cancer Chemotherapy and Pharmacology

, Volume 64, Issue 3, pp 497–507 | Cite as

Synergistic anti-tumor efficacy of lovastatin and protein kinase C-beta inhibitor in hepatocellular carcinoma

  • Won Kim
  • Jung-Hwan YoonEmail author
  • Jung-Ryul Kim
  • In-Jin Jang
  • Yung-Jue Bang
  • Yoon-Jun Kim
  • Hyo-Suk Lee
Original Article

Abstract

Purpose

Hepatocellular carcinoma (HCC) is characterized by hypervascularity and chemoresistance. Protein kinase C (PKC) participates in cancer progression by enhancing anti-apoptotic signals, angiogenesis, and chemoresistance. Statins have a selective anti-cancer effect due to over-expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) in cancer cells, but statins may also activate PKC. Thus, we hypothesized that simultaneous treatment with statin and PKC inhibitor might synergistically enhance their anti-tumor efficacies against HCCs.

Methods

Hepatocellular carcinoma cell growth was assessed using MTS assays, apoptotic cell death by DAPI staining, and apoptotic signaling cascades were explored by immunoblotting. An in vivo model of HCC was established in C3H mice intradermally implanted with MH134 cells. Lovastatin and/or a PKC inhibitor (enzastaurin) was subsequently administered. Anti-tumor efficacies were evaluated by measuring tumor volumes and quantifying apoptotic cells and microvessel densities (MVD).

Results

Co-treatment with lovastatin and enzastaurin was found to synergistically suppress HCC cell growth in vitro. Lovastatin induced HCC cellular apoptosis by activating mitochondrial apoptotic signals, and although enzastaurin alone did not induce apoptosis, its addition significantly enhanced lovastatin-induced apoptosis. This enhanced apoptosis was attributed to increased caspase-9 activation in these cells. Moreover, tumor growth was significantly suppressed in mice co-treated with lovastatin and enzastaurin, and percentages of TUNEL-positive cells were significantly increased and MVDs were significantly decreased in those mice.

Conclusion

Combinatorial treatment with statin and PKC inhibitor was found to enhance anti-tumor efficacy in vivo and in vitro. Further studies are warranted to prove anti-tumor efficacy of this potential therapy in human HCCs.

Keywords

Hepatocellular carcinoma Statin Protein kinase C Apoptosis 

Abbreviations

HCC

Hepatocellular carcinoma

PKC

Protein kinase C

HMG-CoAR

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

MVD

Microvessel densities

TUNEL

Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling

XIAP

X-linked inhibitor of apoptosis protein

Notes

Acknowledgments

This study was supported by the Seoul National University Hospital Research Fund (#03-2006-007), and by the Korean Foundation of Liver Research (2006) and the Korea Health 21 R&D Project (#0412-CR01-0704-0001).

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Won Kim
    • 1
  • Jung-Hwan Yoon
    • 2
    Email author
  • Jung-Ryul Kim
    • 3
  • In-Jin Jang
    • 3
  • Yung-Jue Bang
    • 4
  • Yoon-Jun Kim
    • 2
  • Hyo-Suk Lee
    • 2
  1. 1.Department of Internal MedicineSeoul National University Boramae HospitalSeoulSouth Korea
  2. 2.Department of Internal Medicine and Liver Research InstituteSeoul National University College of MedicineSeoulSouth Korea
  3. 3.Department of Pharmacology and Clinical Pharmacology UnitSeoul National University College of MedicineSeoulSouth Korea
  4. 4.Department of Internal Medicine and Cancer Research InstituteSeoul National University College of MedicineSeoulSouth Korea

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