Volume 14 Supplement 1

6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Open Access

67-kDa laminin receptor and cGMP induced cancer-selective apoptosis

  • Motofumi Kumazoe1 and
  • Hirofumi Tachibana1, 2
BMC Pharmacology and Toxicology201314(Suppl 1):O33

https://doi.org/10.1186/2050-6511-14-S1-O33

Published: 29 August 2013

Background

EGCG ((−)-epigallocatechin-3-O-gallate), a polyphenol in green tea, induces apoptotic cell death in cancer cells without affecting normal cells and several clinical trials have been carried out to evaluate its potential value [1, 2]. 67-kDa laminin receptor (67LR) has been identified as an EGCG receptor [3]. It has recently been demonstrated that overexpressed 67LR in multiple myeloma (MM) mediates EGCG-induced cancer-specific apoptosis [46]. In this study, we revealed that cGMP acts as a cell death mediator of the EGCG-induced anti-MM effect through acid sphingomyelinase (ASM) activation. In this apoptosis pathway, EGCG activated the endothelial nitric oxide synthase (eNOS)/cGMP axis, a well-known mechanism in vascular homeostasis via cancer-overexpressed 67LR. We also demonstrated that cGMP negative regulator, phosphodiesterase 5 (PDE5), was overexpressed in MM cells, and vardenafil, PDE5 inhibitor synergically enhanced the anti-MM effect of EGCG (see Figure 1). This regimen in combination killed MM via overexpressed 67-kDa laminin receptors without affecting normal PBMCs.
Figure 1

EGCG activates the endothelial nitric oxide synthase (eNOS)/cGMP axis via cancer-overexpressed 67LR (A) EGCG induced eNOS activation through 67LR.

Conclusion

In this study, we demonstrate 67LR activated the peculiar apoptotic signalling eNOS/NO/ cGMP/protein kinase Cδ (PKCδ) pathway. Furthermore, we show the upregulation of cGMP is rate-determining process of this cell death pathway. We demonstrate cancer overexpressed negative regulator of cGMP, PDE5 attenuates the cGMP-dependent cell death induced by EGCG. Vardenafil, one of the PDE5 selective inhibitors used for treating erectile dysfunction potentiates anti-cancer effect of EGCG. These results demonstrate that cGMP elevation caused by targeting the overexpressed 67LR and PDE5 in cancer cells may be a useful approach for cancer-specific chemotherapy.

Authors’ Affiliations

(1)
Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University
(2)
Food Functional Design Research Center, Kyushu University

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Copyright

© Kumazoe and Tachibana; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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