Green tea plus erectile dysfunction drug may cause cancer cells to self-destruct??

[Lani]

Green tea and Vardenafil: a killer chemotherapy combo
[Eureka News Service]

Several recent studies have demonstrated that EGCG, a major constituent of green tea, has anti-cancer properties, but the molecular mechanisms underlying its effects are unknown. In this issue of the Journal of Clinical Investigation, Hirofumi Tachibana and colleagues at Kyushu University in Fukuoka, Japan, demonstrate that EGCG activates the 67-kDa laminin receptor, which elevates intracellular levels of the molecule cGMP to induce cell death. Tachibana and colleagues combined EGCG with vardenafil, a drug used to treat erectile dysfunction, which blocks the activity of PDE5, a protein that degrades cGMP. In a mouse model of multiple myeloma, vardenafil potentiated the effects of EGCG to mediate cancer cell death. Chung Yan and Hong Wang of Rutgers University discuss these findings in a companion commentary.

OPEN ACCESS: 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis
[Journal of Clinical Investigation]

The 67-kDa laminin receptor (67LR) is a laminin-binding protein overexpressed in various types of cancer, including bile duct carcinoma, colorectal carcinoma, cervical cancer, and breast carcinoma. 67LR plays a vital role in growth and metastasis of tumor cells and resistance to chemotherapy. Here, we show that 67LR functions as a cancer-specific death receptor. In this cell death receptor pathway, cGMP initiated cancer-specific cell death by activating the PKCδ/acid sphingomyelinase (PKCδ/ASM) pathway. Furthermore, upregulation of cGMP was a rate-determining process of 67LR-dependent cell death induced by the green tea polyphenol (-)-epigallocatechin-3-O-gallate (EGCG), a natural ligand of 67LR. We found that phosphodiesterase 5 (PDE5), a negative regulator of cGMP, was abnormally expressed in multiple cancers and attenuated 67LR-mediated cell death. Vardenafil, a PDE5 inhibitor that is used to treat erectile dysfunction, significantly potentiated the EGCG-activated 67LR-dependent apoptosis without affecting normal cells and prolonged the survival time in a mouse xenograft model. These results suggest that PDE5 inhibitors could be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death.

OPEN ACCESS: COMMENTARY: Cancer therapy combination: green tea and a phosphodiesterase 5 inhibitor?
[Journal of Clinical Investigation]
The major constituent of green tea, (-)-epigallocatechin-3-O-gallate (EGCG), has been shown to have cancer-preventive and therapeutic activities. Numerous molecular targets for EGCG have been proposed, but the mechanisms of its anticancer activities are not clearly understood. In this issue of the JCI, Kumazoe et al. report that EGCG activates 67-kDa laminin receptor (67LR), elevates cGMP levels, and induces cancer cell apoptosis. Furthermore, a phosphodiesterase 5 inhibitor, vardenafil, synergizes with EGCG to induce cancer cell death. This is a provocative observation with important implications for cancer therapy. It also raises several issues for further investigation, such as the mechanism by which EGCG specifically activates 67LR.