ApoG2, a novel inhibitor of antiapoptotic Bcl‐2 family proteins, induces apoptosis and suppresses tumor growth in nasopharyngeal carcinoma xenografts

Abstract

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in South China. It has been reported that overexpression of antiapoptotic Bcl‐2 family proteins in NPC has caused the lack of long‐term efficacy of conventional therapies. Apogossypolone (ApoG2), a novel small‐molecule inhibitor of antiapoptotic Bcl‐2 family proteins, has been discovered as the optimized derivative of gossypol. In this study, we found that in NPC cells, ApoG2 totally blocked the antiapoptotic function of Bcl‐2 family proteins without affecting the expression levels of these proteins. ApoG2 selectively inhibited proliferation of 3 NPC cell lines (C666‐1, CNE‐1 and CNE‐2) that highly expressed the antiapoptotic Bcl‐2 proteins. This inhibitory activity was associated with release of cytochrome c, activation of caspase‐9 and caspase‐3 and apoptosis of sensitive NPC cells. However, ApoG2 had no obvious inhibitory effect on NPC cell line HONE‐1, which expressed antiapoptotic Bcl‐2 and Bcl‐xL at a low level. We further found that ApoG2 effectively suppressed tumor growth of NPC xenografts in nude mice and enhanced the antitumor effect of CDDP (cisplatin) on NPC cells in vitro and in vivo. Immunohistochemical results showed that the expression of CD31 decreased after ApoG2 treatment, which suggested inhibition of angiogenesis in NPC xenografts. Our findings strongly suggest that ApoG2 may serve as a novel inhibitor of Bcl‐2 family proteins and, by targeting these proteins, may become a promising drug for the treatment of NPC. © 2008 Wiley‐Liss, Inc.

Momordica Charantia Lectin, a Type II Ribosome Inactivating Protein, Exhibits Antitumor Activity toward Human Nasopharyngeal Carcinoma Cells In Vitro and In Vivo

“…It seems that MCL-induced mitochondrial damage seems to be the cause rather than the effect of MCL-induced cell death because the phenomenon was detectable as early as 3 hours after treatment (data not shown). These results agree with the prevailing response of most cancer cells exposed to chemotherapeutic components (7,16,39).…”

“…41), and ApoG2 (the synthesized oxidation product of apogossypol from the cotton plant Gossypium; ref. 7,16).…”

“…The in vivo antitumor activity of MCL was studied in athymic nude (nu/nu) mice following the procedure reported elsewhere with modifications (7,16). First, a total of 1 Â 10 7 CNE-2 cells were trypsinized, washed with 1Â PBS, and injected subcutaneously into the right flank of each mouse.…”

“…As mentioned above, TUNEL assay was carried out using an In Situ Cell Death Detection Kit (Roche) as per manufacturer's instructions. The cells were visualized under a light microscope, and the percentage of apoptotic cells under 5 hpf (20Â) was calculated (7,19).…”

“…The coadministration of radiotherapy and adjuvant chemotherapy with cisplatin is the standard treatment for NPC, but the 5-year survival rate is only about 50% to 60%. One obstacle ahead is the high risk of locoregional relapse and distant metastasis (1,7).…”